Targeting Bacterial Resistance: Rational Design and Evaluation of Antibiotic Combinations with Adjuvants

Abstract

Antimicrobial resistance (AMR) has become a major global health concern, posing significant challenges to modern medicine. The diminishing pipeline of novel antimicrobial agents compounds the problem, as big pharmaceutical companies have reduced investments in this area. The rise of AMR has rendered traditional treatment approaches less effective, demanding the identification and development of new therapeutic options. Some bacteria employ enzymes to evade the effects of antimicrobial agents, such as FosA, which degrades fosfomycin, and NDM-1, which hydrolyzes carbapenems. These enzymes pose a critical concern as they target drugs with favorable spectra and are often considered last-resort treatment options. To combat AMR, rational drug design aims to develop compounds that inhibit the enzymes responsible for drug inactivation. Computer-aided drug discovery (CADD) techniques, including structure-based and ligand-based approaches, aid in identifying potential inhibitors. In Chapter 2, the study identifies baicalin, alendronate, risedronate, and zoledronate as FosA inhibitors. When combined with fosfomycin, these compounds demonstrate a reduction in the minimum inhibitory concentration (MIC) of fosfomycin and additive effects. Zoledronate shows the most promise as an adjuvant; however, the combination with fosfomycin exhibits a lower killing rate. Further investigation reveals that a chemical reaction occurred within the mixture, resulting in the degradation of fosfomycin, as confirmed by 31P NMR experiments. Chapter 3 explores the synergy between meropenem with bisphosphonates and various inhibitors against carbapenem-resistant E. coli and K. pneumoniae. The bisphosphonates demonstrated potentiation effects through NDM-1 enzyme inhibition, leading to increased bacterial susceptibility to meropenem. Alendronate and linezolid exhibited synergistic bactericidal activity when combined with meropenem against E. coli, while sutezolid showed promising results.