Penicillin Binding Proteins and beta-Lactamases of Mycobacterium tuberculosis: Reexamination of the Historical Paradigm

Penicillin binding proteins (PBPs) have been extensively studied due to their importance to the physiology of bacterial cell wall peptidoglycan and as targets of the most widely used class of antibiotics, the beta-lactams. The existing paradigm asserts that PBPs catalyze the final step of peptidoglycan biosynthesis, and beta -lactams inhibit their activities. According to this paradigm, a distinct enzyme class, beta-lactamases, exists to inactivate beta-lactams. This paradigm has been the basis for how bacterial diseases are treated with beta-lactams. We tested whether this historical view accurately reflects the relationship between beta-lactams and the PBPs and the beta-lactamase, BIaC, of Mycobacterium tuberculosis. BIaC was the major inactivator of the cephalosporin subclass of beta-lactams. However, the PBPs PonA1 and PonA2 inactivated penicillins and carbapenems more effectively than BlaC. These findings demonstrate that select M. tuberculosis PBPs are effective at inactivating several beta-lactams. Lesser-known PBPs, DacB, DacB1, DacB2, and Rv2864c, a putative PBP, were comparably more resistant to inhibition by all beta-lactam subclasses. Additionally, Rv1730c exhibited low affinity to most beta-lactams. Based on these findings, we conclude that in M. tuberculosis, BIaC is not the only source of inactivation of beta-lactams. Therefore, the historical paradigm does not accurately describe the relationship between beta-lactams and M. tuberculosis. IMPORTANCE M. tuberculosis, the causative agent of tuberculosis, kills more humans than any other bacterium. beta-lactams are the most widely used class of antibiotics to treat bacterial infections. Unlike in the historical model that describes the relationship between beta-lactams and M. tuberculosis, we find that M. tuberculosis penicillin binding proteins are able to inactivate select beta-lactams with high efficiency.