Computational strategies to overcome antibiotic resistance: Exploring novel tetramic acids as Undecaprenyl Pyrophosphate Synthase (UPPS) inhibitors

The rise of multiple antibiotic resistance is a critical obstacle to the design and development of novel antimicrobial agents. The historical paradigm of monotherapies (i.e., drugs acting on single biological targets) has been replaced in recent years by multi-targeting therapies (e.g., antibiotic combinations and hybrids) which act on two or more targets. The efficacy of this multi-targeting approach is increased if the targets belong to divergent metabolic pathways, thereby minimising the likelihood of simultaneous dual-target resistance. Thus, the development of novel antibiotic scaffolds capable of inhibiting multiple, diverse enzymes is critical to addressing antibiotic resistance. Computational techniques, molecular dynamics (MD) simulations in particular, play a fundamental role in structurally elucidating protein-drug binding interactions and in predicting their binding affinities, tasks which are essential to the antibiotic drug design process. In this thesis, the mode of inhibition of selected 3-carboxamide and 3-acyl tetramic acids (TAs), which exhibit dual inhibition of bacterial undecaprenyl pyrophosphate synthase (UPPS) and RNA polymerase (RNAP), is investigated within UPPS using computational methods. UPPS is an essential bacterial enzyme involved in peptidoglycan synthesis of the bacterial cell wall and is hence a prime antibiotic drug target. In addition, the TA inhibitors are not only novel but contain a single chemical scaffold which is multi-targeting, both of which represent desirable attributes of the latest antibiotic drugs. In the absence of an X-ray crystal structure of the UPPS-TA complex, this work elucidates the most probable binding site of the TAs in UPPS, employing rigid docking and MD-based free energy calculations. The area of antibiotic drug design may benefit greatly from such computational predictions since the structural basis for inhibition of UPPS by the TAs remains poorly understood.