Question

capreomycin has been shown to be bactericidal in vitro among the anti-TB drugs against non-replicating tubercle bacilli: Why is it important to have a TB drug that is active against a non-replicating bacterium?

Answer 1

Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance.

If the immune response flags, Mtb can resume replication and give rise to tuberculosis, a contagious disease that kills more people than any other bacterial infection. Nonreplicating Mtb are also problematic in clinically active tuberculosis (Boshoff and Barry, 2005).

The acidic phagosomal environment and “nitroxidative” (Lancaster, 2004) chemistry generated by the macrophages in which Mtb resides and the deprivation of oxygen and nutrients that may result from the accumulation of inflammatory cells at infected sites can each keep Mtb from replicating (Voskuil et al., 2003).

Nonreplicating Mtb display nonheritable antibiotic resistance, also called phenotypic tolerance, a phenomenon that pertains to most members of a bacterial population starved for nutrients, as well as to a small, nonreplicating fraction of a population undergoing logarithmic expansion (Levin and Rozen, 2006).

Durable cure of tuberculosis requires eradication of both replicating and nonreplicating Mtb (McCune et al., 1966). During treatment of tuberculosis, nonreplicators termed “persisters” may be responsible for relapse rates that only fall below 5% when chemotherapy is extended for many months. Such prolonged treatment is difficult to sustain, and its interruption fosters the emergence of mutants with heritable drug resistance