Deeper insights into the action of class C β-lactamases against cephalosporins through molecular docking and MD simulation studies

Antimicrobial resistance is a global crisis that has been exacerbated by the inappropriate use of antibiotics. Drug-resistant bacteria are a major menace to public health and treatment of multidrug resistant bacterial infections is extremely challenging. One major contributor to high antibiotic resistance of bacteria is the increased production of β-lactamases which are responsible for cleavage of β-lactams. Therefore, targeting β-lactamases with potential inhibitors could be one of the important strategies in combating antimicrobial resistance. However, in order to target β-lactamases, we need to have a better understanding of the underlying interactions between the β-lactamases and the β-lactam antibiotics. In this regard, we have performed a molecular docking and MD simulation-based analysis to study interaction between class C β lactamases forming proteins i.e., CMY, ACT, AmpC and FOX with five generations of cephalosporins namely Cefepime, Ceftraoline, Ceftriaxone, Cefuroxime, and Cephalexin. The three-dimensional structure of ACT-1, AmpC, CMY-37, and FOX-1 proteins were modelled and validated, and were subsequently docked with each of the five generations of cephalosporins. Based on the molecular docking and MMGBSA results, ACT-ceftraoline, AmpC-ceftraoline, CMY-ceftraoline, and FOX-cefepime complexes were considered for molecular dynamics simulation, which revealed that among the four complexes, FOX-cefepime was the most stable. Our work provides useful insights towards structure-based drug development against FOX-1, which have an impact on bacterial resistance. The interactions between β-lactamase and cefepime can be exploited to build novel therapeutic treatments against the FOX-1 β-lactamases. Further validation of this is essential, preferably through in vitro and in vivo studies.