Investigating the Role of Metabolism for Antibiotic Combination Therapies in Pseudomonas aeruginosa

Abstract

Antibacterial resistance poses a severe threat to public health; an anticipated 14-fold increase in multidrug-resistant (MDR) bacterial infections is expected to occur by 2050. Contrary to antibiotics, combination therapies are the standard of care for antiviral and anticancer treatments, as synergistic drug–drug interactions can decrease dosage and resistance development. In this study, we investigated combination treatments of a novel succinate dehydrogenase inhibitor (promysalin) with specific inhibitors of metabolism and efflux alongside a panel of clinically approved antibiotics in synergy studies. Through these investigations, we determined that promysalin can work synergistically with vancomycin and antagonistically with aminoglycosides and a glyoxylate shunt pathway inhibitor at subinhibitory concentrations; however, these cooperative effects do not reduce minimum inhibitory concentrations. The variability of these results underscores the complexity of targeting metabolism for combination therapies in antibiotic development.

Immunometabolic Regulation of Bacterial Infection, Biofilms, and Antibiotic Susceptibility

“…These conclusions have also been achieved studying other major opportunists, like P. aeruginosa . By enhancing the bacterial TCA cycle and the generation of a proton gradient across the membrane, fumarate augmented the P. aeruginosa susceptibility to the aminoglycoside, tobramycin, which is highly used in clinics to treat hard-to-eradicate infections [ 169 , 170 ]. Importantly, the utilization of fumarate to facilitate bacterial clearance during antibiotic therapy is consistent with the inactivating effects of derivatives of this factor on the host effector response, like dimethylfumarate [ 168 , 169 , 171 ].…”

Potent Inhibition of E. coli DXP Synthase by a gem-Diaryl Bisubstrate Analog

“…Antimicrobial resistance predates the discovery of antibiotics and is an unavoidable threat in the treatment of infectious diseases. To combat resistance, new antibacterial strategies are needed that are selective for pathogens and avoid toxicity to the host microbiome, which can negatively impact human health. − Agents that target central metabolic processes are increasingly sought − and have the potential to exert narrow-spectrum activities. ,− However, this target space is relatively underexploited owing to the complexities in developing central metabolism targets and the perceived difficulties in selectively targeting bacterial metabolism over host metabolism. ,,, Essential to bacterial central metabolism and absent in humans, 1-deoxy- d -xylulose 5-phosphate synthase (DXPS) emerged as a promising antibacterial target with the potential to offer opportunities for developing narrow spectrum approaches. ,− …”