Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update

The global control and management of tuberculosis (TB) is faced with the formidable challenge of worsening scenarios of drug-resistant disease. Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of TB. It plays a key role in reducing TB relapse rates, shortening the course of the disease treatment from 9–12 months to 6 months, and the treatment of patients infected with bacillary strains that are resistant to at least isoniazid and rifampicin. Additionally, it is the only first-line anti-TB drug most likely to be maintained in all new regimens, which are aimed at reducing the treatment period of susceptible, multi-drug resistant and extensively drug-resistant TB. It has a preferential sterilizing activity against non-replicating persister bacilli with low metabolism at acid pH in vitro or in vivo during active inflammation where other drugs may not act so well. PZA seem to have a non-specific cellular target and instead, exerts its anti-mycobacterial effect by disrupting the membrane energetics, the trans-translation process, acidification of the cytoplasm and perhaps coenzyme A synthesis, which is required for survival of Mycobacterium tuberculosis (MTB) persisters. Indeed, the emergence of MTB strains resistant to PZA represents an important clinical and public health problem. The essential role of PZA in TB treatment underlines the need for accurate and rapid detection of its resistance. This article presents an updated review of the molecular mechanisms of drug action and resistance in MTB against PZA, commenting on the several research gaps and proposed drug targets for PZA.