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Microbial genetics

Exploiting genomics, genetics and chemistry to combat antibiotic resistance

Nature Reviews Genetics volume 4, pages 432–441 (2003)Cite this article

Key Points

  • The prevalence and spread of antibiotic resistance is an increasingly serious problem that hampers the effective treatment of infectious diseases.

  • Resistance to antibiotics is caused, in part, by the genetics of bacteria. Large population sizes mean that many resistance mutations pre-exist, and the ability to transfer genetic material between species facilitates the spread of resistance.

  • A second cause of antibiotic resistance is the overuse, misuse and suboptimal use of antibiotics, which result in selection for the emergence and spread of resistant strains.

  • As part of a strategy to combat antibiotic-resistance problems in medicine there is an urgent need to discover and develop new antibiotics against which there is no pre-existing resistance.

  • Bacterial genomics is providing information to identify potential new targets for antibiotic screening programmes. Molecular genetics techniques are being applied to validate potential antibiotic targets.

  • Combinatorial chemistry, combinatorial biology and structural biology are being used to create and to optimize lead compounds for antibiotic development. Combinatorial chemistry is also being used to generate effective analogues of existing antibiotics the usefulness of which is being threatened by increasing resistance.

  • Alternative strategies to the development of new antibiotics are being pursued in parallel. These include the development of inhibitors of resistance mechanisms, optimizing antibiotic usage, developing effective vaccines and exploring the usefulness of bacteriophage therapy.

Abstract

To address the worsening problem of antibiotic-resistant bacteria there is an urgent need to develop new antibiotics. Comparative genomics and molecular genetics are being applied to produce lists of essential new targets for compound screening programmes. Combinatorial chemistry and structural biology are being applied to rapidly explore and optimize the interactions between lead compounds and their biological targets. Several compounds that have been identified from target-based screens are now in development, but technical and economic constraints might result in a trickle, rather than a flood, of new antibiotics onto the market in the near future.

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Figure 1: The VanA gene cluster that confers vancomycin resistance.
Figure 2: Target-based antibiotic discovery and development — the basic strategy.

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Acknowledgements

The author is supported by grants from the Swedish Research Council (Medicine and Natural Sciences), the European Union and Leo Pharma. I thank the anonymous reviewers for their positive and helpful suggestions to improve the manuscript. This paper is dedicated to the late Pat Hughes.

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  1. Department of Cell and Molecular Biology, Box 596, The Biomedical Center, Uppsala University, Uppsala, S-751 24, Sweden

    Diarmaid Hughes

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Glossary

COMBINATORIAL CHEMISTRY

Methods that can, in a controlled manner, result in the synthesis of numerous chemical variants of a molecule.

TWO-COMPONENT REGULATORY SYSTEM

A signal-transduction system that consists of a sensor protein that senses and responds to an external signal, and which acts on a response-regulator protein that transmits the signal to other components of the cell.

ENTEROCOCCI

Gram-positive cocci bacteria, which include Enterococcus faecium and Enterococcus faecalis.

LATERAL GENE TRANSFER

The transfer of DNA, frequently cassettes of genes, between organisms.

BIOLOGICAL FITNESS

A relative measure of the ability of a particular group of bacteria to compete successfully in a particular environment.

MOLECULAR TYPING

The use of molecular genetic techniques — for example, multiplex PCR, pulse-field gel electrophoresis, Southern blotting and multilocus sequence typing — to genetically compare and characterize bacterial genomes.

TRANSPOSON MUTAGENESIS

The use of transposons to generate (knock-out) mutations.

SUICIDE VECTOR

A vector (plasmid) that is unable to replicate in a particular host and is maintained only if it recombines into the host genome.

PEPTIDE DEFORMYLASE

An essential bacterial metalloenzyme that deformylates the N-formylmethionine of newly synthesized bacterial polypeptides.

PBP2A

A penicillin-resistant transpeptidase that is encoded by mecA in methicillin-resistant S. aureus strains.

GLYCOPEPTIDES

The antibiotic class to which vancomycin belongs.

MULTIDRUG EFFLUX

The process by which efflux pumps bind and efflux a variety of structurally dissimilar compounds from the cell.

BROAD-SPECTRUM ANTIBIOTICS

Antibiotics that kill or inhibit the growth of phylogenetically distant bacterial species, for example, Gram-negative and Gram-positive bacteria.

MUTANT-PREVENTIVE CONCENTRATION

(MPC). The antibiotic concentration that prevents the growth of bacteria carrying single mutations to resistance.

MINIMAL INHIBITORY CONCENTRATION

(MIC). The minimal amount of antibiotic that is required to prevent the growth of a bacterial strain under defined conditions.

CONJUGATE VACCINE

A vaccine in which the bacterial polysaccharide antigen is coupled to a protein carrier that can be processed and presented to T cells bearing specific receptors for the protein complex.

SEROTYPE

A bacterial strain that is classified on the basis of its surface antigens.

BACTERIOPHAGE

A virus that infects, grows on and can kill specific strains of bacteria.

PHASE III CLINICAL TRIALS

The assessment of efficacy and side-effects; generally involves hundreds of patients enrolled at different clinics nationwide or worldwide.

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Hughes, D. Exploiting genomics, genetics and chemistry to combat antibiotic resistance. Nat Rev Genet 4, 432–441 (2003). https://doi.org/10.1038/nrg1084

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