ETHICS EXERCISE SEVENTEEN
Jan Fields is leaving her office to start her daily round of sales calls when the telephone rings. Her plans for the morning go awry as the angry voice on the other end of the line demands to know the status of an order. The order represents Jan’s biggest sale to date and the first her company has made with a major franchise.
Jan quickly contacts Ken McBride. Ken feels his breath catch in his chest. As he had predicted earlier in the month, production has fallen behind schedule. Now he has a unique part on hand that is needed for two different orders. He has to decide whether to use it to fill a regular customer’s order, which is legitimately far ahead of the one in question and urgently needed, or to honor Jan’s frantic request.
Ken could reduce his immediate stress level and save Jan’s day by bumping the regular customer’s order. This move would cause a serious problem for the valued old customer. However, no business would be lost, of course, because the old customer would have no way of knowing that its order has been set aside to accommodate a new customer in the hope of generating future sales.
[“Boxed In, An Ethical Dilemma”; Business Communication, Strategies and Skills; 4th Ed., The Dryden Press, 1991]
Assignment:
How could the company reduce or avoid such situations in the future?
In: Operations Management
- All the following are reported as current liabilities except:
Notes payable due in 3 years
Deferred revenues
Notes payable due in 8 months
Accounts payable
- In each succeeding payment on installment note:
The amount of interest expense is unchanged
The amount of interest expense increases
The amount of interest expense decreases
The amounts paid for both interest and principal increase proportionately
- Which of the following is considered to be a Land Improvement asset?
A sprinkler system
A warehouse
A printing press
A dump truck
- The sale of gift cards by a company is direct example of:
Deferred revenues
Installment notes
Current portion of long-term debt
Sales tax payable
- Flamingo Company borrows $30,000 using a five-year, long-term installment note payable. The rate on the note is percent and Flamingo agrees to make monthly payments of $566.14. Which of the following statements is correct about Flamingo’s first payment?
Note payable reduction is $125.00 and interest is $441.14
Note payable reduction is $441.14 and interest is $125.00
Note payable reduction is $123.16 and interest is $442.98
Note payable reduction is $442.98 and interest is $123.16
- Young Company is involved in a lawsuit. The liability that could arise as a result of this lawsuit should be recorded on the books of Young if:
The likelihood of losing the lawsuit is reasonably possible and the amount is reasonably estimable.
The likelihood of losing the lawsuit is probable and the amount is not reasonably estimable.
The likelihood of losing the lawsuit is remote and the amount is reasonably estimable.
The likelihood of losing the lawsuit is probable and the amount is reasonably estimable.
In: Accounting
Week Two: Statement of Ethics
Compose a statement of ethics of 500 words.
Whereas the
professional philosophy statement (work statement) from week one
focused on specific knowledge, skills and work experience, the
primary focus of the statement of ethics is to share a little about
the values, beliefs, or life experiences that are relevant to your
chosen career. For the purpose of this assignment, a general
statement of ethics based on your field is fine, but feel free to
imagine you are applying to a specific business and tailor the
statement accordingly. RELATED TO R.N. NURSES
| Ethical strengths to consider: |
| Strong Work Ethic |
| Reliable |
| Team player |
| Honest |
| Flexible |
| Professional |
| Resourceful |
Consider the following questions to help guide you:
A few additional points:
Just as with the professional philosophy statement from week one, it is recommended that you begin with an introductory paragraph, followed by one or more body paragraphs, and to end with a concluding paragraph that summarizes your overall perspective and will leave a lasting impression. Feel free to include a brief quotation in the introduction or conclusion if you find one that nicely illustrates your viewpoint.
Blogs should include a visual presence. Consider adding a graphic, photo, or other visual element to your blogs to earn full credit on the rubric. Remember, do not attach a files. Type and insert media directly into the textbox.
In: Nursing
Learning Outcome: please long answer and no hand writing
3. Describe the impact of diversity and the changing workforce on organizations and organizational performance.
4. Examine the role of HR as a strategic partner in an organization
Assignment Workload:
This assignment is an individual assignment.
The word count for this assignment must be between 800 to 1000 words
Case Study
B.R Investments is a reputed finance company having 15 branches in different part of the country. In the home office there are more than 200 employees. This company has a performance rating under which the employees are rated at six months intervals by a committee of two executives. Graphic scales have been used as means of appraisal. The qualities considered are responsibility, initiative, and interest in work, leadership potential, co-operative attitude and community activity. After the performance is evaluated, the ratings are discussed with the concerned employees by their immediate boss who counsels them. The ratings aroused to influence promotions and salary adjustments the employees and also as a criterion for assigning further rating for them.
Recently three employees of the company called on the company’s president to express their dissatisfaction with the ratings they had received. Their scores and composite ratings had been discussed with them. Because their ratings were comparatively low, they had been denied annual increments in salary. Approximately, two thirds of all the employees received such increments. The aggrieved employees argued that their ratings did not accurately represent their qualifications or performance. They insisted that “community activity” was not actually a part of their job and that what they do off the job is none of the company’s business. They expressed their opinion that employees should organize union and insist that salary increase be automatic.
The threat of a union caused concern to the officers of the company. This particular experience convinced the top officers that ratings may represent a serious hazard to satisfactory relationship with employees. Even the chief executive finds that performance appraisal is a dangerous source of friction and its hazards outweigh its values; so it should be discontinued altogether.
Questions:
1. How far do you agree with the management that performance appraisal should be discontinued?
2. If you were the HR manager, how would you tackle the situation?
3. What modifications would you suggest in the performance appraisal system of the company?
In: Economics
Read the information below and then complete the 2018 Schedule A.
John and Julia are married and have two children. John works as a graphic designer for a design firm and Julia is a massage therapist. They own a vacation home in Colorado that is used 30% for personal purposes (assume it is used 70% as a rental property and the income and expenses related to the rental have been accounted). During the year they receive $600 in reimbursements from their medical plan and report $5,500 of investment income (included in AGI). They contributed stock, with a fair market value of $3,000, which they acquired in 2005 at a cost of $1,700 to Ohlone College. Their gambling winnings for the year were $1,000 and are included in their adjusted gross income. Their adjusted gross income for the year is $98,000 and they provide you with the following data:
Automobile insurance $ 1,450 / Homeowners insurance 625
Life insurance 1,000 / Disability insurance 375
Health insurance premiums (paid on an after tax basis) 1,600
Country club dues 1,800 / Health club dues 750
Hospital 5,000 / Doctor 1,275
Massage Therapists (they pay to receive messages, not related to Julia’s job) 700
Dentists 3,750 / Prescription drugs 275
Over-the-counter drugs 460 / State taxes withheld 8,475
Property taxes (ad valorem) 400 / Investment interest 1,600
Mortgage interest (primary residence) 6,850
Real estate taxes (primary residence) 2,240
Mortgage interest (vacation residence - unallocated) 2,700
Real estate taxes (vacation residence - unallocated) 1,350
Charitable contributions (cash; they have receipts) 7,750
Charitable contribution (clothes at FMV) 100
Subscriptions to investment journals 175
Dues to professional organizations 375
Tax prep fees 600 / Investment advice 525
Parking at work 190 / Safe-deposit box 75
Gambling losses 650
Unreimbursed employee business expenses (the full amounts paid and unreimbursed):
Airfare 500 / Lodging 450
Meals 290 / Entertainment 280
Incidentals 250
1. How many personal and dependency exemptions will they receive?
2. The box by 5a should be checked. T F
3. The box by 8a should be checked. T F
4. The box on line 18 should be checked. T F
In: Accounting
Correct the following sentences – we are only practicing when and when not to use a colon.
For the following sentences, DO NOT add or remove words or rearrange the sentences.
You should ONLY correct punctuation. You may have to add or remove colons. Sometimes a comma should be replaced with a colon or a colon should be replaced with a comma. It is also possible that you will end-up with a sentence that has neither comma nor colon.
In: Accounting
1.Brian is putting together a balance worksheet and just finished entering the balances of the general ledger accounts into the trial balance section of the worksheet.
After making sure that the trial balance is accurate, Brian will prepare the __________ section, followed by the __________ section of the worksheet.
a.)income statement; balance sheet
b.)balance sheet; closing entries
c.)adjusting entries; adjusted trial balance
d.)adjusted trial balance; income statement
2 Which of the following statements is NOT a characteristic of a trial balance?
a.)All account totals are summarized.
b.)The report is made public.
c.)Posting errors are identified.
d.)Debit totals and credit totals are compared.
3 Which scenario below correctly describes an unearned revenue adjustment entry?
a.)Brian accounted for the printer ink cartridges that he used during the month for his various orders.
b.)Brian made the next adjustment and recorded $2,975 to be paid to graphic artist contractors at the end of the month, when paychecks were sent out.
c.)Brian was halfway through a project that involved creating and printing advertisement posters for a local hardware store. He would not be paid until the project was complete.
d.)Brian was recently hired to create and print brochures and business cards for the customer's new landscaping company. Brian was given a down payment for his work, but had not yet begun work
4 Sharon would make an adjustment entry to __________ to record the $500 her company received from a customer to perform future services.
Suppose that before the adjusting entry, the balance in this account was $2,725. After the adjusting entry, the ending balance will be __________.
a.)accounts receivable; $2,225
b.)prepaid expenses; $2,225
c.)unearned revenue; $3,225
d.)accrued revenue; $3,225
5 In the general journal, Amy saw a record in the owner's drawing account indicating that a partner withdrew $675 from her firm last month.
Which of the following is a closing general journal entry that Amy will make related to this withdrawal?
a.)Amy will not make a closing general journal entry related to this withdrawal.
b.)Amy will record a credit of $675 to the cash account.
c.)Amy will record a debit of $675 to the owner's capital account.
d.)Amy will record a credit of $675 to accounts payable.
In: Accounting
Assignment
Write a program using turtle graphics which writes your initials, or any other three unique letters, to the display. Look to your program for lab 1 for reminders of how to use turtle graphics.
Functions that must be written:
def drawLetter (x, y, letterColor): Write three functions, one for three unique letters. Personally, I would write drawA, drawR, and drawS. Each function must draw that letter to the screen. The x and y values determine the upper left-hand location for the start of the letter. Ensure that each letter takes the same amount of space, both vertically and horizontally. The letterColor parameter will be a string used to determine the color of the letter – use it to set the fillcolor, and maybe pencolor. You can also set pencolor to “black” to create an outline of the letter. In the Turtle Graphics Resources link in blackboard I have a link to valid turttle graphic colors.
Each function can have one, and only one, goto command. If drawing a letter which requires two “shapes,” such as a “O” with a two circles you can use a second goto. The initial goto should position the turtle in the upper left-hand location of the letter to be drawn. It might be smart to ensure that you know what direction the turtle is pointing before starting to draw the letter. All of the actual drawing must be done with basic movements, such as forward, backward, left, or right. Remember to use penup and pendown to ensure you only draw the desired lines.
def drawShadowedLetter (x, y, letterColor, offset): Write three more functions, one for each letter (mine would be drawshadowedT, drawShadowedL, and drawShadowedS). These functions will use your drawLetter functions, once using letterColor, and once adding offset to the x and y values and using “black” as the color. This will create a “shadowed” letter. These three functions will not be doing any actual drawing, all of the graphics work will be done in the drawLetter functions.
In the main program, draw your initials to the screen twice. The first time write your initials to the screen using the drawLetter functions. Somewhere else on the display, write your initials to the screen using the drawShadowedLetter functions.
In: Computer Science
Question: From the Article Below, write a review of the current status of development of antibiotics." I do not have the figures!"
Article: Antibiotic discovery in the twenty-first century: current trends and future perspectives
New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment.
Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for
new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent
with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However,
many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially
effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities
have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use.
Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected
examples, we offer our view on the future of antibiotic discovery.
The Journal of Antibiotics advance online publication, 16 June 2010; doi:10.1038/ja.2010.62
Keywords: antibiotics; natural products; pipeline
Medical progress in the prevention and treatment of many diseases,
which have resulted in significantly increasing life expectancy, may be
put at risk without the introduction into clinical practice of new
antibiotics effective against multidrug-resistant (MDR) pathogens.
Although most stakeholders agree that new antibiotics could tackle
this unmet medical need, opinions vary on how new antibiotics could
be discovered and brought into the market in a cost-effective manner.
1–3 Two considerations would probably meet with unanimous
consensus: the golden era of antibiotic discovery is gone and it will not
be repeated; and genomics, combinatorial chemistry and highthroughput
screening do not represent the magic bullet to fill the
pipeline with new developmental drug candidates. In this respect, it is
important to underline the contribution that natural products,
especially those of microbial origin, can provide to antibiotic discovery,
as advocated by Demain4,5 on several occasions. The decreasing
number of drugs approved for clinical use, year after year, suggests
that the ‘ailing pharmaceutical industry’ is not yet following the
‘prescription’ of Demain,6 as spelled out in 2002.
The purpose of this review is to highlight some of today’s features of
antibiotic discovery in the context of the current medical needs and
the existing pipeline of antibacterial agents in clinical development.
Our main focus will be on chemical classes that, if developed into
drugs, would be new to the clinic. However, these classes would not
necessarily be new to science. For example, a ‘look-back’ strategy was
applied to antibiotics discovered during the golden era, which were
then reexamined using contemporary tools in the light of current
medical needs.7 Although some important breakthroughs have also
been made in identifying new promising drug candidates from
synthetic origin, for reason of space, and in the spirit of the important
contributions to the field by Demain, we would limit ourselves
to antibiotics of microbial origin and their derivatives reported
since 2005.
CURRENT ANTIBIOTIC PIPELINE
Infections due to methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant Enterococcus faecium (VRE) and fluoroquinolone-
resistant Pseudomonas aeruginosa are rapidly increasing in US
hospitals, and even more frightening is the recent occurrence of
panantibiotic-resistant infections, involving Acinetobacter species,
MDR P. aeruginosa and carbapenem-resistant Klebsiella species.8,9
Although antibiotic resistance continues to grow in hospitals and in
the community, involving both Gram-positive and Gram-negative
pathogens, the number of newly approved agents has been decreasing,
with only six new antibiotics approved since 2003.
In the late 90s, following the global concern regarding the rapid
increase in MRSA, many companies redirected their attention to target
Gram-positive pathogens, particularly MRSA, VRE and penicillinresistant
Streptococcus pneumoniae, as evidenced by the commercial
and clinical success of linezolid and daptomycin, the only antibiotics
belonging to new classes introduced in clinical practice since the early
1960s. However, most antibiotics currently under development for
Gram-positive infections are improved derivatives of existing drugs
(see Table 1). As vancomycin has been increasingly used for the
treatment of a wide range of infections, second-generation glycopep-
tides with improved profile over vancomycin were developed. Among
them, telavancin, a once-a-day derivative of vancomycin, was
approved by the US Food and Drug Administration (FDA) in 2009.
Oritavancin, derived from the vancomycin-related glycopeptide chloroeremomycin,
is highly active against VRE strains and shows a long
plasma half-life. However, in 2008, the FDA did not authorize its
commercialization. The long-acting glycopeptide dalbavancin, a derivative
of the teicoplanin-related glycopeptide A40926, was also not
approved by FDA, because of insufficient clinical evidence of efficacy.
If approved, dalbavancin would be the first antibiotic to be administered
once weekly.10
Resistance to methicillin in S. aureus is mediated by the production
of a penicillin-binding protein with reduced affinity for b-lactams. The
most recent cephalosporins, ceftobiprole and ceftaroline (Table 1),
have been specifically designed to enhance activity against MRSA and,
thanks to their oral availability, are particularly attractive for the
community setting. Ceftobiprole is quickly bactericidal against a wide
range of Gram-positive pathogens, including MRSA and VRE and has
been approved in Canada and Switzerland.11 However, early in 2010,
the FDA did not grant market authorization to ceftobiprole, and later
the European authority issued a negative opinion on this compound.
Ceftaroline, which is active against most Gram-positive pathogens
with the exclusion of enterococci, has completed phase III studies and
may be submitted for FDA approval.12 Both cephalosporins, however,
lose potency against MRSA compared with methicillin-susceptible
S. aureus strains. The injectable carbapenem PZ-601 has shown potent
activity against drug-resistant Gram-positive pathogens, including
MRSA, and is currently undergoing phase II studies.13
After the success of linezolid, many new oxazolidinones are being
developed for Gram-positive infections. Radezolid14 and torezolid15
are currently in phase II trials, whereas RWJ-416457 has completed the
phase I trial. Despite the fact that the use of fluoroquinolones has been
associated with increased incidence of MRSA,16 several new members
of this class are under development: delafloxacin, nemonoxacin,
zabofloxacin and WCK-771 (Table 1) are the most advanced.
The extensive use of fluoroquinolones and other wide-spectrum
antibiotics such as cephalosporins, by affecting the normal gut flora,
has led to the rapid diffusion of Clostridium difficile-associated
diarrhea, particularly in elderly and immunocompromised patients.
Difimicin, currently in phase III, and ramoplanin, with phase II
completed, are microbial products under development for prevention
and treatment of C. difficile-associated diarrhea, acting locally by
decolonizing the gut (Table 1).
Other compounds which have completed phase I clinical trials
include the oral and injectable pleuromutilin BC-3205,17 the FabI
inhibitor AFN-1252 targeting staphylococcal infections18 and the
lipopeptide friulimicin (Table 1).19
The scenario is even more disappointing for compounds targeting
Gram-negative pathogens, in which old drugs have been revamped for
new uses, and none of them has reached phase III yet (Table 1).
Ceftazidime is a marketed cephalosporin being developed in combination
with NXL104, a representative of a new class of b-lactamase
inhibitors,20 which renders cephalosporin effective against most
b-lactamase-producing enterobacteria. If approved, this combination
would be the first alternative to piperacillin/tazobactam. NXL104 is
also under investigation in combination with ceftaroline.21 CXA-101 is
a ceftazidime-like compound with improved stability against the
AmpC b-lactamase, but it shows no improvements against MDR
P. aeruginosa,22 unless administered in combination with tazobactam.
The new aminoglycoside ACHN-490, effective against pathogens
resistant to this class, has recently completed phase I.23 The new
monobactam BAL-30072, stable against metalloenzymes, is ready to
start clinical development against difficult-to-treat Gram negatives,
including Pseudomonas and Acinetobacter.24
The increasing spread of MDR Gram-negative pathogens, particularly
P. aeruginosa, Acinetobacter spp. and some Enterobacteriaceae has
renewed the interest toward narrow-spectrum compounds, to avoid
other clinical conditions associated with the use of broad-spectrum
antibiotics. However, because of a long history of success in the
empirical treatment of infections, many hospitals lack rapid and
effective tools for identifying etiological agents. This limitation poses
significant hurdles for the clinical development of narrow-spectrum
compounds.
APPROACHES LEADING TO NEW ANTIBIOTIC CLASSES
It is generally agreed that the best way to overcome the decreasing
efficacy of existing antibacterial agents is to introduce into practice
compounds belonging to classes that are new to the clinic. Microbial
sources can provide a rich reservoir of such compounds, and the
different approaches used usually aim at discovering either a novel
class or an improved variant of a poorly explored class. However,
this must be carried out in a high background of many known
compounds, some of which are encountered in random screening
programs at a relatively high frequency. Thus, the discovery of an
antibacterial agent belonging to a new chemical class or an improved
variant of an existing class is a rare event, and the approaches
described below reflect strategies designed and implemented to
capture this rare event. Appropriate strategies include retrieving
microbial strains from underexplored environments, screening new
microbial taxa, mining microbial genomes and using innovative
assays. These strategies have led to some novel chemical classes, as
illustrated in Figure 1.
As an example of the first strategy, investigation of deep-sea
sediment samples led to the discovery of abyssomicins (Figure 1),
which are polycyclic antibiotics from the new marine actinomycete
taxon Verrucosispora.25 The compounds were discovered using a simple
agar diffusion assay, which involved pursuing antibiotics the action of
which could be reverted upon addition of p-aminobenzoic acid.
Abyssomicins represent a new chemical class, and preliminary studies
indicate that they act as substrate mimics of chorismate. Interestingly,
only abyssomicin C and its atrop stereoisomer show antibiotic activity
against Gram-positive bacteria, including MDR S. aureus.26
An additional example of a new chemical class discovered by
screening new taxa is represented by thuggacins (Figure 1), which
are thiazole-containing macrolides produced by the myxobacteria
Sorangium cellulosum and Chondromyces crocatus.27 These compounds
show activity against Mycobacterium tuberculosis and their target
appears to be the electron transport chain.
Another successful approach has been exploring microbial genomes
for the presence of secondary metabolite pathways. As the corresponding
genes are organized in clusters and bioinformatic tools allow
a reasonable prediction of the pathway product, this bioactivityindependent
approach can directly target structural novelty. On a
pioneering work of this type, scientists at Ecopia Biosciences (now
Thallion Pharmaceuticals, Montreal, QC, Canada) identified ECO-
02301, a linear polyene from Streptomyces aizunensis with antifungal
activity28 and ECO-0501, a glycosidic polyketide from Amycolatopsis
orientalis with activity against Gram-positive pathogens, including
MDR isolates (Figure 1).29 In a similar approach, a novel cyclic
lipopeptide, designated orfamide (Figure 1), was identified from the
Pseudomonas fluorescens genome.30 In this case, the bioinformatic
prediction that the peptide contained four leucine residues suggested
feeding with 15N-Leu, which facilitated compound purification and
characterization. Orfamide shows a moderate antifungal activity
against amphotericin-resistant strains of Candida albicans and may
prove beneficial in agriculture and crop protection.
Another important strategy for discovering new classes of antibiotics
has been the implementation of increased-sensitivity assays in
screening programs. One such approach relied on the antisense
technology. When the level of a desired bacterial target is depleted
by overexpression of the cognate antisense mRNA, the strain becomes
hypersensitive to compounds acting on that target. By using a target
against which few compounds are known to act, the increased
sensitivity of the assay should allow the identification of compounds
routinely missed with growth inhibition assays on the wild-type
strain.31 One assay involved the FabH/FabF enzyme, required for
fatty acid biosynthesis in bacteria. Antimicrobial activities were
detected by agar diffusion in a two-plate assay, in which one plate
was inoculated with S. aureus carrying the antisense construct and the
other plate with an S. aureus control. Different inhibition halos in the
two plates indicated an increased sensitivity of the ‘antisense strain.’
After screening 4250 000 microbial product extracts, the assay led to
the identification of a new chemical class that includes platensimycin
(Figure 1), produced by Streptomyces platensis, and related compounds.
Platensimycin shows antibacterial activity against Grampositive
pathogens, including MDR strains, and was also effective in
an experimental model of infection.32
In another increased-sensitivity assay, a high-throughput screening
program was implemented to identify inhibitors of a cell-free translational
system affecting steps other than elongation. The assay made
use of a model ‘universal’ mRNA that could be translated with similar
efficiency by cell-free extracts from bacterial, yeast or mammalian cells.
The rationale behind the approach was to use a sensitive assay and to
discard frequently encountered compounds using a polyU-based assay.
This program led to the identification of GE81112 (Figure 1), a novel
tetrapeptide produced by a Streptomyces sp., which targets specifically
the 30S ribosomal subunit by interfering with fMet-tRNA binding to
the P-site.33 The compound was highly effective against a few Grampositive
and Gram-negative strains, if grown in minimal or chemically
defined medium, suggesting active uptake by the cells.34
The above examples illustrate how different approaches can lead to
novel antibiotic classes. Usually, when unexploited microbial diversity
is accessed, there is no need for specific, high-sensitivity assays.
Whichever the approach chosen, there is no guarantee of success.
The reader is referred to a recent review for suggestions on how to
increase the probabilities of success.35
IMPROVED VARIANTS FROM MICROBIAL SOURCES
New variants of known classes can be found by screening microbial
strains, by varying cultivation procedures or by manipulating the
biosynthetic pathway. There is an increasing amount of literature
related to pathway manipulation and this trend is likely to continue as
methodological advancements result in increased success rates. In
some cases, the desired variant might not be a more active compound,
but a molecule carrying functional groups suitable for further chemical
modifications. As the antibiotics in clinical use belong to a few
classes, which have been extensively explored by screening and
chemical modification, there is probably little space for finding
improved variants within those classes. We provide selected examples
of microbial strains producing improved variants of chemical classes
not yet in clinical use.
Lantibiotics, which are ribosomally synthesized peptides that
undergo posttranslational modifications to yield the active structures
containing the typical thioether-linked (methyl)lanthionines, are produced
mostly from strains belonging to the Firmicutes and, to a lesser
extent, to the Actinobacteria. Their antimicrobial activity is limited to
Gram-positive bacteria. The prototype molecule is nisin, discovered in
the 1920s and used as a food preservative for440 years.36 Lantibiotics
with antibacterial activity are divided into two classes according to
their biogenesis: lanthionine formation in class I compounds requires
two separate enzymes, a dehydratase and a cyclase, whereas a single
enzyme carries both activities for class II lantibiotics. Until recently,
the occurrence of class I compounds was limited to the Firmicutes (see
below). Although compounds from both classes exert their antimicrobial
activity by binding to Lipid II, they do so by binding to
different portions of this key peptidoglycan intermediate.
As lantibiotics bind Lipid II at a site different from that affected by
vancomycin and related glycopeptides, they are active against MDR
Gram-positive pathogens and have attracted attention as potential
drug candidates. The compound NVB302, a derivative of deoxyactagardine
B (Figure 2a) produced by a strain of Actinoplanes liguriae, is
currently a developmental candidate for the treatment of C. difficileassociated
diarrhea.37 Independently, a screening program, designed to
detect cell-wall-inhibiting compounds turned out to be very effective
in identifying lantibiotics from actinomycetes.38 It consisted of identifying
extracts active against S. aureus but inactive against isogenic
L-forms, discarding extracts the activity of which was abolished by
b-lactamases or by excess N-caproyl-D-alanyl-D-alanine. Among the
new lantibiotics identified, the most active compound was NAI-107
(Figure 2a), produced by Microbispora sp.39 This compound represents
the first example of a class I lantibiotic produced by actinomycetes. It
is currently a developmental candidate for the treatment of nosocomial
infections by Gram-positive pathogens.40 The same screening
program led to the identification of additional class I lantibiotics from
actinomycetes. Among them, the compound 97518 (Figure 2a),
structurally related to NAI-107,41 afforded improved derivatives by
chemical modification.42 Another interesting advancement in the
lantibiotic field has been the discovery of two-component lantibiotics
produced by members of the class Bacilli. The best characterized
compound is haloduracin43,44 (Figure 2a), whereas lichenicidin has
been proposed from genomic studies but has not yet confirmed by
structural elucidation.45 Although their antimicrobial activities have
not been described in detail, recent work suggests similar activities for
haloduracin and nisin.44
Thiazolylpeptides are highly modified, ribosomally synthesized
peptides that inhibit bacterial protein synthesis by affecting either
one of two targets: elongation factor Tu, as for GE2270 and related
compounds; or the loops defined by 23S rRNA and the L11 protein,
exemplified by thiostrepton. Most thiazolylpeptides show potent
activity against Gram-positive pathogens, yet their poor solubility
has limited clinical progress, and only a derivative of GE2270 has
entered clinical trials for the topical treatment of acne.46 Novel
members of this class have been described (Figure 2b): thiomuracins47
belong to the subgroup targeting EF-Tu, with an antibacterial profile
similar to GE2270; thiazomycin48 and philipimycin,49 which target the
50S subunit, show high activity against Gram-positive strains, and a
similar profile to thiostrepton.
For ribosomally synthesized peptides, such as lantibiotics and
thiopeptides, new representatives can be generated by site-directed
mutagenesis of the corresponding structural genes. Libraries of new
molecules have been obtained, many of which, as in the examples of
actagardine50 and thiocillin,51 retained antibiotic activities comparable
with those of the parent molecule.
CHEMICAL DERIVATIVES
Many papers have been published in the past 5 years reporting
chemical programs aimed at overcoming the prevailing resistance
mechanisms and/or to improve the drug profile of known microbial
products. Novel approaches included the use of new tools, such as
click chemistry and total synthesis. For the classical approach of semisynthesis,
we will limit the examples to selected compounds not yet in
clinical use.
Click chemistry is a new synthetic approach that can accelerate drug
discovery by using a few practical and reliable reactions. A ‘click’
reaction must be of wide scope, giving consistently high yields with
various starting materials; it must be easy to perform, insensitive to
oxygen or water and use only readily available reagents; finally,
reaction work-up and product isolation must be simple, without
chromatographic purification.52 As an example, this approach was
used to produce new lipophilic teicoplanin and ristocetin aglycons
with improved activity against Gram-positive bacteria, including
VRE.53 For aminoglycosides, which usually require multiple protection–
deprotection steps to selectively manipulate the desired amino
and hydroxyl groups, click chemistry allowed the transformation
of neomycin B into several novel building blocks that were used for
the specific modification of the ring systems, thus generating new
neomycin analogs the biological activity of which is currently under
investigation.54
For some low-molecular-weight compounds, total synthesis has
become available and will be useful to design preliminary SAR for new
classes of antibiotics (such as platensimycin) or to access new
derivatives for already known classes (such as tetracyclines). Indeed,
the novel scaffold and intriguing biological property of platensimycin
captured the interest of several research groups, which reported
different elegant total syntheses.55 In addition, medicinal chemistry
studies have been conducted, and the design, synthesis and biological
evaluation of several platensimycin analogs incorporating varying
degrees of molecular complexity have been reported.56–58 Preliminary
data indicate that certain modifications of the intricate cage region can
be made without detrimental effects on potency, whereas even small
modifications of the benzoic acid region result in a drastic loss of
activity (Figure 1). Another remarkable chemical improvement in the
synthesis of natural product analogs was a short and enantioselective
synthetic route to a diverse range of 6-deoxytetracycline antibiotics
(Figure 3a). This new approach targeted not a single compound but a
group of structures with the D ring as a site of structural variability.
A late-stage, diastereoselective C-ring construction was used to couple
structurally varied D-ring precursors with an AB precursor containing
much of the essential functionality for binding to the bacterial
ribosome. Results of antibacterial assays and preliminary data
obtained from a murine septicemia model show that many of the
novel tetracyclines synthesized have potent antibiotic activities. This
synthetic platform gives access to a broad range of tetracyclines that
would be inaccessible by semi-synthesis and provides a powerful
engine for the discovery of new tetracyclines.59,60
Even on larger molecules, semi-synthetic and synthetic chemistry
has been successfully applied to study and optimize lead compounds.
The lipoglycodepsipeptide ramoplanin (Figure 3b) is 2–10 times more
active than vancomycin against Gram-positive bacteria and maintains
full activity against VRE and all MRSA strains. However, its systemic
use has been prevented by its low tolerability at the injection site,
apparently related to the length of the fatty acid side chain.
To overcome this problem, the fatty acid side chain was selectively
removed and replaced with different carboxylic acids. Many derivatives
showed an antimicrobial activity similar to that of the precursor,
and a significantly improved local tolerability.61 The recently
described, fully synthetic lactam analog of ramoplanin showed the
same biological activity as the natural product. Moreover, a set of
alanine analogs, obtained by total synthesis, has provided insights into
the importance of individual amino-acid residues on ramoplanin
activity. The MICs of each alanine-containing analog parallels its
ability to bind Lipid II. Apart from positions 5, 6 and 9, which can
tolerate alanine substitutions, MICs increased 415-fold upon alanine
replacement, with dramatic effects observed for positions 4, 8, 10 and
12. The new data thus confirm the importance of the ornithine
residues at positions 4 and 10, with the latter directly involved in
target binding, most likely by ion pairing with the diphosphate of
Lipid II.62,63
The mannopeptimycins, which were originally isolated in the late
1950s from Streptomyces hygroscopicus, have been recently revived
because of their promising activity against clinically important Grampositive
pathogens, including S. pneumoniae, MRSA and VRE. They
also bind to Lipid II, but in a manner different from ramoplanin,
mersacidin and vancomycin. Multiple approaches have been used to
optimize the mannopeptimycin activity profile, including selective
chemical derivatization, precursor-directed biosynthesis and pathway
engineering. The SAR data have shown that substitution of a hydrophobic
ester group on the N-linked mannose or serine moieties
suppressed antibacterial activity, whereas hydrophobic acylation on
either of the two O-mannoses, particularly the terminal mannose,
significantly enhanced activity. AC98-6446 (Figure 3b) represents an
optimized lead obtained by adamantyl ketalization of a cyclohexyl
analog prepared by cyclohexylalanine-directed biosynthesis. AC98-
6446 showed superior antimicrobial potency and properties, both
in vitro and in vivo.7,64
Laspartomycin is active against VRE and MRSA strains. Recently,
enzymatic cleavage of its lipophilic moiety allowed the synthesis of
various acylated derivatives (Figure 3b), even if none was more potent
than the parent antibiotic.65 The cyclic heptapeptide GE23077 is a
potent and selective inhibitor of bacterial RNA polymerase
that, probably because of its hydrophilicity, is unable to cross
bacterial membranes. New derivatives obtained by modifying different
moieties were reported. Although many of them retained activity
on the enzyme, none showed a significant antibacterial activity
apart from marginal inhibition of Moraxella catarrhalis growth
(Figure 3b).66
FUTURE PERSPECTIVES
This brief and nonexhaustive excursus on the present and future
pipeline of antibacterial agents for treating human diseases provides
opportunities for additional considerations. The first is that, of the
antibiotics under clinical development (Table 1), 67% are natural
products themselves, or natural product-derived compounds, a percentage
perfectly in line with that found with exisiting drugs.67
The second consideration is that the major players in antibacterial
development are small companies, which are not deterred by the small
market size for these drugs. However, it should be noted that a
significant number of the compounds listed in Table 1 were not
discovered by small companies, but actually represent projects abandoned
by large pharmaceuticals companies. Thus, it remains to be
seen whether small biotechs will dedicate sufficient resources and be
successful in discovering and developing novel antibacterial agents.
In this relatively grim scenario, microbial products continue to
provide new chemical classes or unexpectedly active variants of
chemical classes already known to science. New technologies can
now provide access to unexplored microbial diversity or to hypersensitive
assays to detect bioactive compounds. Furthermore, the information
derived from rapidly accessing the genome of many microbial
strains can provide new routes to natural product discovery, as well as
making more effective traditional, bioassay-based screening efforts.
In our opinion, no single technology will represent the magic bullet
for antibiotic discovery, but only the painstaking integration of a
multidiscplinary team with profound knowledge of microbiology,
chemistry and bioinformatics will ultimately lead to new antibacterial
agents of medical relevance and commercial success.
In: Biology
06. Testing a new insect repellent. (Adapted from McClave, Benson, & Sincich, 12th edition, page 556). A study in the Journal of the American Mosquito Control Association (Mar. 1995) investigated whether a tent sprayed with a commercially available 1% permethrin formulation would protest people, both inside and outside the tent, against biting mosquitoes. Two canvas tents — one treated with permethrin, the other untreated — were position 25 meters apart on flat, dry ground in an area infested with mosquitoes. Eight people participated in the experiment, with four randomly assigned to each tent. Of the four stationed at each tent, two were randomly assigned to stay inside the tent (at opposite corners) and two to stay outside the tent (at opposite corners). During a specified 20-minute period during the night, each person kept count of the number of mosquito bites received. The goal of the study was to determine the effect of both Tent type (treated or untreated) and the Location (inside and outside) on the mean mosquito bite count.
The data for the study are shown in the table below. The summary values for the factors are given with A = Tent type and B = Location.
| Inside | Outside | |
| Treated |
4 7 |
8 11 |
| Untreated |
6 10 |
24 16 |
A1=30, A2=56, B1=27, B2=59, AB11= 11, AB12= 19, A21=16, AB22= 40
CM=924.5
Fill this table out
| Source | df | SS | MS | F |
| Treatments | ||||
| Tent Type | ||||
| Location | ||||
| Tent Type*Location | ||||
| Error | ||||
| Total |
These are the correct answers, but I don't understand how we got this.
| Source | df | SS | MS | F |
| Treatments | 3 | 244.5 | 81.5 | 6.8980 |
| Tent Type | 1 | 84.5 | 84.5 | 10.4490 |
| Location | 1 | 128 | 128 | 2.6122 |
| Tent Type*Location | 1 | 32 | 32 | |
| Error | 4 | 49 | 12.25 | |
| Total | 7 | 293.5 |
In: Statistics and Probability