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Opinion — anti-infectives

Where will new antibiotics come from?

Abstract

There is a constant need for new antibacterial drugs owing to the inevitable development of resistance that follows the introduction of antibiotics to the clinic. When a new class of antibiotic is introduced, it is effective at first, but will eventually select for survival of the small fraction of bacterial populations that have an intrinsic or acquired resistance mechanism. Pathogens that are resistant to multiple drugs emerge around the globe, so how robust are antibiotic discovery processes?

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Figure 1: Structures of naturally and synthetically derived antibiotics.
Figure 2: Principal targets for antibiotic action.

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FURTHER INFORMATION

Christopher Walsh's laboratory

TIGR

United States Center for Disease Control

United States Food and Drug Administration

Wellcome Trust Sanger Institute

Glossary

ANTIMETABOLITE

A structural analogue of metabolites that inhibit enzymes that normally recognize the metabolite as substrate.

COMBINATORIAL CHEMISTRY

The application of synthetic methods, often in high-throughput format, to combine molecular fragments to create many structurally related congeners.

HETEROCYCLIC DRUGS

A drug molecule that contains carbon, nitrogen, oxygen and sulphur atoms in ring structures — typically five- or six-membered rings.

MACROLIDE

Macrocyclic (ring greater than six carbons) structures in which the cyclization occurs by lactone formation between the two ends of the molecule. The macrolactone erythronolide provides the scaffold in the antibiotic erythromycin.

METAGENOME

The collective genomes of soil bacteria.

NATURAL-PRODUCT SCAFFOLD

The structural and architectural platform of natural products that can be decorated, for example, by glycosylation or with synthetic modifications.

NON-RIBOSOMAL PEPTIDE

A peptide that is made from amino acids, often amino acids that are not found in proteins, that are assembled by multimodular enzymes not involving RNA templates or the ribosome for peptide-bond formation.

POLYKETIDE

A natural product that is assembled from malonyl CoA units through intermediates with many ketone (polyketonic) groups that allow for directed reactivity to product structures.

SORTASE

An enzyme in the cell membrane of Gram-positive bacteria that sorts proteins to be displayed in the outer membrane by covalently connecting those proteins to the peptidoglycan layer.

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Walsh, C. Where will new antibiotics come from?. Nat Rev Microbiol 1, 65–70 (2003). https://doi.org/10.1038/nrmicro727

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  • DOI: https://doi.org/10.1038/nrmicro727

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