Loss of a Class A Penicillin-Binding Protein Alters β-Lactam Susceptibilities in Mycobacterium tuberculosis
| Autor: | James Gomez, Samantha Wellington, Carl N. Wivagg, Deborah T. Hung |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Carbapenem Penicillin binding proteins Tuberculosis medicine.drug_class 030106 microbiology Cephalosporin Antibiotics Biology beta-Lactams beta-Lactam Resistance Subclass Microbiology Mycobacterium tuberculosis Structure-Activity Relationship 03 medical and health sciences polycyclic compounds medicine Penicillin-Binding Proteins Loss function Gene Expression Regulation Bacterial biochemical phenomena metabolism and nutrition biology.organism_classification medicine.disease Mutagenesis Insertional Infectious Diseases beta-Lactamase Inhibitors medicine.drug |
| Zdroj: | ACS Infectious Diseases. 2:104-110 |
| ISSN: | 2373-8227 |
| Popis: | Recent studies have renewed interest in β-lactam antibiotics as a potential treatment for Mycobacterium tuberculosis infection. To explore the opportunities and limitations of this approach, we sought to better understand potential resistance mechanisms to β-lactam antibiotics in M. tuberculosis. We identified mutations in the penicillin-binding protein (PBP) ponA2 that were able to confer some degree of resistance to the cephalosporin subclass of β-lactams. Surprisingly, deletion of ponA2 also confers resistance, demonstrating that β-lactam resistance can spontaneously arise from PBP loss of function. We show that ponA2 mutants resistant to the cephalosporin subclass of β-lactams in fact show increased susceptibility to meropenem, a carbapenem that is known to target l,d-transpeptidases, thereby suggesting that in the absence of PonA2, an alternative mode of peptidoglycan synthesis likely becomes essential. Consistent with this hypothesis, a negative genetic selection identified the l,d-transpeptidase ldtMt2 as essential in the absence of ponA2. The mechanism of β-lactam resistance we outline is consistent with emerging models of β-lactam killing, while the investigation of ponA2 downstream and synthetic lethal genes sheds light on the mechanism of cell wall biosynthesis and the interaction between conventional PBPs and l,d-transpeptidases. |
| Databáze: | OpenAIRE |
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