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

Abstract

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

• Authors: Gaurav Kumar, Christos Galanis, Hunter R Batchelder, Craig A Townsend, Gyanu Lamichhane
• Journal: mSphere (mSphere) Vol. 7 Issue 1 Pg. e0003922 (02 23 2022) ISSN: 2379-5042 [Electronic] United States
• PMID: 35196121 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Bacterial Agents
• Penicillin-Binding Proteins
• Peptidoglycan
• beta-Lactams
• beta-Lactamases

Topics

• Anti-Bacterial Agents (pharmacology)
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (genetics)
• Penicillin-Binding Proteins (genetics)
• Peptidoglycan
• beta-Lactamases (genetics)
• beta-Lactams (pharmacology)