Mycobacterium tuberculosis fatty acid synthase I and ribosomal protein S1 (FAS-I / RpsA)

Mycobacterium tuberculosis Fatty acid synthase I (FAS-I) and Ribosomal protein S1 (RpsA) are distinct bacterial proteins identified as the primary molecular targets of pyrazinoic acid (POA), the active metabolite of the essential anti-tuberculosis drug pyrazinamide [1, 2]. FAS-I is a large, multifunctional enzyme complex that catalyzes the de novo synthesis of long-chain fatty acids, which serve as precursors for the mycolic acids required for the mycobacterial cell wall [1]. RpsA is a vital component of the 30S ribosomal subunit involved in translation initiation and the trans-translation pathway, a mechanism used by bacteria to rescue stalled ribosomes and degrade incomplete proteins [2, 3]. The inhibition of these targets by POA leads to the disruption of membrane integrity and protein synthesis, which is particularly effective against slow-growing or dormant bacilli in acidic environments [3]. While pyrazinamide is a cornerstone of modern tuberculosis therapy, resistance often arises through mutations in the pncA gene (which activates the prodrug) or, less frequently, in the rpsA or panD genes [2, 4]. Clinical use of drugs targeting these proteins is associated with risks of hepatotoxicity and hyperuricemia, requiring careful patient monitoring [4].

Other names

FAS1RpsA30S ribosomal protein S1Fatty acid synthetaseFAS-IFAS-I / RpsA

Pyrazinoic acid (POA) inhibits Fatty acid synthase I (FAS-I), thereby blocking the synthesis of fatty acid precursors for mycolic acids [1]. Additionally, POA binds to Ribosomal protein S1 (RpsA), inhibiting the trans-translation process which is essential for protein quality control and survival in non-replicating persistent Mycobacterium tuberculosis [2, 3].