Mycobacterium tuberculosis ribosomal protein S1 (RpsA) (RpsA)

Mycobacterium tuberculosis ribosomal protein S1, commonly known as RpsA, is a vital component of the bacterial 30S ribosomal subunit [1, 2]. It plays a crucial role in translation initiation by binding to the upstream leader sequences of messenger RNA and is also essential for the trans-translation process [2, 3]. Trans-translation is a ribosome-rescue mechanism that allows the bacterium to clear stalled ribosomes, which is particularly important for the survival of non-replicating or persistent bacilli [2, 7]. RpsA has been identified as a primary target for pyrazinoic acid (POA), the active metabolite of the first-line anti-tuberculosis drug pyrazinamide (PZA) [1, 3]. By binding to the C-terminal domain of RpsA, POA inhibits trans-translation, leading to the accumulation of stalled ribosomes and eventual cell death in persistent populations [1, 2]. This unique mechanism of action allows PZA to shorten the duration of tuberculosis chemotherapy by targeting dormant bacteria that other drugs cannot reach [2, 11]. However, the role of RpsA as a PZA target remains a subject of scientific debate, as some recent studies have failed to replicate the binding interaction between POA and RpsA [4, 6, 9]. Despite this controversy, mutations in the rpsA gene continue to be recognized as a significant mechanism of clinical resistance to pyrazinamide [3, 13, 14].

Other names

RpsA30S ribosomal protein S1Ribosomal protein S1

Pyrazinoic acid (POA), the active form of pyrazinamide, binds to the C-terminal domain of RpsA, specifically interacting with residues such as Lys303 and Phe307 [1]. This binding inhibits the trans-translation process by competing with tmRNA, thereby preventing the rescue of stalled ribosomes [1, 2]. This inhibition is particularly effective against non-replicating persister bacilli, which rely on trans-translation for survival under stress [2, 11].