Key Points
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Over the past 30 years, there has been a widespread emergence of resistance to antibiotics in pathogenic bacteria. This resistance is now a serious threat to global public health and could undermine the major advances that had been previously achieved in the treatment of infection.
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The success rate has been extremely low for the identification of novel antibacterial agents by concerted genomic and high-throughput screening initiatives, meaning that a new strategy is now required to develop the next generation of antibiotics. Although structure-based drug discovery is still in its infancy for antibacterial-drug discovery, the growing number of molecular targets for which structural information is available makes this approach increasingly attractive.
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The starting point for all structure-based design work, whether ligand or protein based, is the choice of a suitable target. Antimicrobial-drug targets should be essential, have a unique function in the pathogen and exhibit an activity that can be altered by a small molecule.
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Three main methods are available to assist in the identification of new putative ligands on the basis of structural information: substrate-inspired inhibitor design, virtual high-throughput screening and de novo design of inhibitor scaffolds. Structure-based approaches to the identification of new inhibitors of both classical and novel bacterial targets will increase in future years. However, it should also be remembered that an improved understanding of the molecular basis by which existing antibacterial agents act may provide insights for new structure-based approaches to drug discovery.
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Although still in its infancy, the technology described in this Review may provide the new classes of antibacterial drugs that will be required to fight infection in the twenty-first century and beyond.
Abstract
The modern era of antibacterial chemotherapy began in the 1930s, and the next four decades saw the discovery of almost all the major classes of antibacterial agents that are currently in use. However, bacterial resistance to many of these drugs is becoming an increasing problem. As such, the discovery of drugs with novel modes of action will be vital to meet the threats created by the emergence of resistance. Success in discovering inhibitors using high-throughput screening of chemical libraries is rare. In this Review we explore the exciting opportunities for antibacterial-drug discovery arising from structure-based drug design.
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Acknowledgements
Work in the authors' laboratories is supported by grants from the UK Medical Research Council (MRC), the UK Biotechnology and Biological Sciences Research Council (BBSRC), Heart Research UK and the European Community's Seventh Framework Programme FP7 (under grant agreement HEALTH-F4-2007-201924, EDICT Consortium).
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Supplementary information S2 (table) | Source information for docking and vHTS programs and other resources (PDF 204 kb)
Glossary
- Pharmacophore
-
A set of structural features in a molecule that are recognized at a receptor site and are responsible for the biological activity of the molecule.
- Algorithm
-
A finite sequence of instructions; an explicit, step-by-step procedure for solving a problem, often used for calculation and data processing.
- Scoring function
-
A fast, approximate mathematical method that is used to predict the strength of the non-covalent interaction (also referred to as the binding affinity) between two molecules following docking. Scoring functions are normally parameterized (or trained) against a data set consisting of experimentally determined binding affinities between molecular species that are similar to the species that the user wishes to predict. For predictions of protein–ligand affinities, the tertiary structure of the protein, the active conformation of the ligand and the binding mode must be known.
- Force field
-
The functional form and parameter sets used to describe the potential energy of a system of particles.
- Free energy
-
The calculated difference between the internal energy of a system and the product of its absolute temperature and entropy.
- Linear-regression analysis
-
Any approach to modelling the relationship between one or more variables denoted Y and one or more variables denoted X, such that the model depends linearly on the unknown parameters to be estimated from the data.
- Toxicity
-
The degree to which a substance is able to damage an exposed organism.
- ADME
-
Absorption, distribution, metabolism and excretion. An acronym in pharmacokinetics and pharmacology describing the disposition of a pharmaceutical compound in an organism.
- Log P
-
The partition coefficient (P), usually expressed as a log value, is a measure of the hydrophobic character of a substance, such that P = concentration of the substance in octanol / concentration of the substance in water.
- On-the-fly optimization
-
A fast, dynamic procedure used to make a system or design as effective or functional as possible.
- DNA gyrase
-
An enzyme that unwinds DNA so that the DNA can duplicate.
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Simmons, K., Chopra, I. & Fishwick, C. Structure-based discovery of antibacterial drugs. Nat Rev Microbiol 8, 501–510 (2010). https://doi.org/10.1038/nrmicro2349
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DOI: https://doi.org/10.1038/nrmicro2349
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