Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance

Abstract

Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome. To assess our design strategy, we tested all candidates for in vitro inhibitory activity and then evaluated them in vivo with several antibiotic-resistant strains to determine minimal inhibitory concentrations. The predicted best candidate is synthetically more accessible, exhibits higher solubility and binding affinity to the ribosome, and is up to 56 times more active against resistant pathogens than telithromycin. Notably, the best compounds designed by us show activity, especially when combined with the membrane-weakening drug colistin, against Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli, which are the three most critical targets from the priority list of pathogens of the World Health Organization.

Multiscale QM/MM modelling of catalytic systems with ChemShell

“…Other complex biomolecular targets in recent work include membrane enzymes, 163 protein-protein interactions, 164 and the bacterial ribosome. 165 QM/MM methods are now widely applied to the study of excited electronic states, in tandem with electronic structure software packages capable of time-dependent density functional theory or wavefunction-based excited state calculations. Light-sensitive proteins that have been simulated with Chem-Shell in recent studies include a wide range of rhodopsins, [166][167][168][169][170][171][172][173] photosystem II, [174][175][176] calcium-regulated photoproteins, 177 green fluorescent protein, 178 the phototoxic protein KillerRed, 179 bacterial phytochromes, 180,181 and cyanobacteriochromes.…”

“…Other complex biomolecular targets in recent work include membrane enzymes, 163 protein–protein interactions, 164 and the bacterial ribosome. 165…”

Current State‐of‐the‐Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products

“…The generation and modeling of theoretical structures hold the promise of identifying promising targets of chemoenzymatic methods. Once an area of untapped potential, recent advances in computational power and the ability to access designer macrolides have made this method of drug development a reality; a recent study utilized in silico modeling to generate a panel of C3‐O‐acyl derivatives of the macrolide clarithromycin and validated their antibacterial efficacy via in vivo tests against bacterial cell lines [106] . This method of drug development resulted in the construction of several new compounds which reduced the IC 50 values by as much as 3‐fold.…”

“…Once an area of untapped potential, recent advances in computational power and the ability to access designer macrolides have made this method of drug development a reality; a recent study utilized in silico modeling to generate a panel of C3-O-acyl derivatives of the macrolide clarithromycin and validated their antibacterial efficacy via in vivo tests against bacterial cell lines. [106] This method of drug development resulted in the construction of several new compounds which reduced the IC 50 values by as much as 3-fold. Further goals involve the ability to completely derivatize macrolides at every position, the uptake of new synthetic feedstocks, and the use and synthesis of novel extender units.…”

UniversalQM/MMapproaches for general nanoscale applications

“…Typical areas of application are biomolecules, 22 metalloenzymes, 8,23 symmetry defects in metals, 24 covalent 25 and metal 26 organic frameworks, carbonnanotubes 27 and graphene, 28 solution chemistry in studies of spectroscopy, 29 light induced processes, 30,31 solvation [32][33][34][35] and adsorption 35 chemistry, excited states, 36 and nonadiabatic dynamics. 37 Also, quantum classical hybrid models have been leveraged to accelerate explicitly atomistic drug design efforts, 38,39 with the aim to improve on the accuracy of classical MM models and to cover nonstandard chemistry by a QM approach. 40 The QM-cluster approach 41,42 is an alternative approach to deal with a large nanoscopic system.…”