Review Article | Published:

Platforms for antibiotic discovery

Nature Reviews Drug Discovery volume 12, pages 371387 (2013) | Download Citation

Abstract

The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.

Key points

  • The pace of antibiotic discovery has slowed down while resistance to bacteria is increasing.

  • Biofilms harbouring drug-tolerant persisters often lead to untreatable chronic infections.

  • Looking for untapped sources, such as uncultured bacteria, and developing rapid dereplication are likely to resuscitate the natural product discovery platform.

  • A focus on species-specific compounds will provide a discovery platform, as the probability of finding such molecules is higher than the probability of discovering broader-spectrum antimicrobial compounds.

  • Establishing rules that guide the penetration of molecules into bacteria will revive the rational design and high-throughput screening of synthetic compounds.

  • Prodrugs that form reactive molecules within bacterial cells are capable of broad-spectrum and sterilizing activity.

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Acknowledgements

A. Bissell is acknowledged for his help in preparing the manuscript. The work in the author's laboratory (described in this review) has been supported by the following grants: T-R01AO085585, RO1GM061162 and ARO W9911NF- 09-1-0265; and grant 42792 from the Bill & Melinda Gates Foundation.

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  1. Department of Biology and Antimicrobial Discovery Center, Northeastern University, Boston, Massachusetts 02115, USA.

    • Kim Lewis

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Competing interests

The author is a member of the scientific advisory board of NovoBiotic Pharmaceuticals, Arietis Corporation and Seres Health.

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Correspondence to Kim Lewis.

Glossary

Persisters

Metabolically quiescent cells that neither grow nor die when exposed to bactericidal concentrations of antibiotics.

High-throughput screening

(HTS). An automated instrumental process for detecting the binding or activity of hundreds of thousands of compounds to an isolated receptor target or whole cells, thereby identifying worthwhile leads for development.

Rational drug design

A strategy by which drug molecules are developed based on the analysis of the three-dimensional structure of a protein interacting with a ligand.

Lipinski's 'rule of five' guidelines

Guidelines (from Lipinski's analysis of the World Drug Index) identifying several key properties that should be considered for small molecules that are intended for oral delivery. These properties are: molecular mass <500 Da, number of hydrogen-bond donors <5; number of hydrogen-bond acceptors <10; and calculated octanol–water partition coefficient (an indication of the ability of a molecules to cross biological membranes) <5.

MDR efflux

Multidrug-resistant (MDR) efflux; an active transport system for the removal of several structurally non-related antibiotics from cells. The major facilitator (MF) family of MDRs are drug or proton antiporters present in all bacteria that are primarily responsible for efflux of hydrophobic cations and have some role in protecting bacteria from disinfectants, but not from systemically used antibiotics. The resistance nodulation cell division (RND) MDRs of Gram-negative bacteria are very broad- spectrum and will extrude most amphipathic compounds. These MDRs span the entire cell envelope and extrude compounds across the outer membrane — the main penetration barrier for antibiotics.

Microbiota

The entire collection of microorganisms (bacteria, archaea and fungi, as well as protozoa and viruses) that are resident on or in the host.

Operons

Loci consisting of two or more genes that are transcribed as a unit and expressed in a coordinated manner.

Dereplication

The rapid identification of known compounds to avoid the duplication of efforts (also called counterscreening).

Transcription profiling

Large-scale studies of the expression of genes at the mRNA level, typically with microarray technology.

Polymyxin B nonapeptide

A small cationic peptide that disrupts the outer membrane of Gram-negative bacteria by binding to lipopolysaccharide.

Quorum sensing

A system by which bacteria communicate. Signalling molecules — chemicals that are similar to pheromones that are produced by an individual bacterium — can affect the behaviour of surrounding bacteria.

Biofilms

A cell–cell or surface-adherent assemblage of microorganisms that are encased in an extracellular matrix of self-produced polymers and exhibit distinctive phenotypes.

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https://doi.org/10.1038/nrd3975