Work

Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis

Year: 2017

Type: article

Abstract: Aims Inhibition of β-lactamase by clavulanate (Clav) sensitizes multi-and extensively drug-resistant Mycobacterium tuberculosis ( Mtb ) strains towards β-lactams such as amoxicillin (Amox). However, the underlying mechanism of how Mtb responds to Amox-Clav combination (Augmentin; AG) is not characterized. Results We integrated global expression profiling with the protein-protein interaction landscape and generated a genome-scale network of Mtb in response to AG. In addition to specific targets ( e.g., peptidoglycan biosynthesis and β-lactamase), the response to AG was also centered on redox-balance, central carbon metabolism (CCM), and respiration in Mtb. We discovered that AG modulates superoxide levels, NADH/NAD + balance and mycothiol redox potential ( E MSH ) of Mtb . Higher intra-mycobacterial E MSH potentiates mycobactericidal efficacy of AG, whereas lower E MSH induces tolerance. Further, Mtb responds to AG via a redox-sensitive transcription factor, WhiB4. MtbΔwhiB4 displayed higher expression of genes involved in β-lactam resistance along with those mediating respiration, CCM and redox balance. Moreimportantly, WhiB4 binds to the promoter regions and represses transcription of genes involved in β-lactamase expression in a redox-dependent manner. Lastly, while MtbΔwhiB4 maintained internal E MSH , exhibited greater β-lactamase activity and displayed AG-tolerance, overexpression of WhiB4 induced oxidative shift in E MSH and repressed β-lactamase activity to aggravate AG-mediated killing of drug-sensitive and –resistant strains of Mtb . Innovation and Conclusions This work demonstrate that efficacy of β-lactam\β-lactamase inhibitor combination can be attenuated by elevating mycobacterial antioxidant capabilities and potentiated by impairing redox buffering capacity of Mtb . The functional linkage between β-lactams, redox balance, and WhiB4 can be exploited to potentiate AG action against drug-resistant Mtb .

Source: eLife

DOI: 10.7554/elife.25624