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The future challenges facing the development of new antimicrobial drugs

Nature Reviews Drug Discovery volume 1, pages 895–910 (2002)Cite this article

Key Points

  • The global emergence of resistance to antibacterial agents is increasingly limiting the effectiveness of current drugs.

  • There is no obvious solution to this problem, although the development of new antimicrobial agents, the extension of the life of current agents by improved educational methods, vaccination and other methods of disease control are being pursued.

  • However, the past record of rapid, widespread emergence of resistance to newly introduced antimicrobial agents indicates that even new families of antimicrobial agents will have a short life expectancy.

  • This Review covers four approaches to the development of new systemic antimicrobial agents: classic screening; structural changes to existing agents; genome hunting; and a novel route that targets non-multiplying, latent bacteria. The primary focus is the last approach, which is hoped to lead to new drugs that will reduce the rate of emergence of resistance to antimicrobial agents.

  • Resistance to antimicrobial agents could be due to an innate property of the bacterium, or a consequence of mutation or gene transfer.

  • So far, all current antimicrobial agents have been developed against multiplying bacteria However, multiplication is not the main state in which microbes exist — they spend most of their time not multiplying. This non-multiplying state is resistant to all known antimicrobial drugs.

  • Non-multiplying bacteria prolong treatment. For example, in bacterial pneumonia, the microbes consist of at least two populations that exist simultaneously; namely, multiplying and non-multiplying. Multiplying bacteria are killed quickly by antimicrobial agents, whereas non-multiplying or slowly multiplying bacteria tolerate repeated doses of antimicrobial agents and lead to the need for a conventional prolonged course of drugs.

  • Prolonged suboptimal bactericidal concentrations can lead to the emergence of resistance, not usually in the target pathogen, but in the normal flora in the gut, skin and throat. Long courses of antimicrobial agents are more likely to encourage the emergence of resistance than shorter courses.

  • Prolonged courses of antimicrobial agents are also associated with a reduction in patient compliance, which leads to an increased rate of resistance.

  • One possible solution to the current problems might be to shorten the duration of chemotherapy by targeting non-multiplying bacteria with new antimicrobial agents. Drug libraries should be screened against non-multiplying bacteria to discover new antibacterial drugs that kill them.

  • If new drugs that target non-multiplying bacteria are used in combination with those that target multiplying bacteria, the emergence of antimicrobial resistance to the new drugs could potentially be slowed, and the drugs could remain useful for longer than at present.

  • The authors propose a new set of standards for testing of antimicrobial agents against non-multiplying bacteria. These are more suitable than minimum inhibitory concentration (MIC).

Abstract

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance — targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.

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Figure 1
Figure 2: Antibacterial drug targets.
Figure 3: Mechanisms of genetic resistance to antimicrobial agents.
Figure 4: Prolonged chemotherapy can lead to an enhanced rate of emergence of resistance to antibacterial agents.
Figure 5: Non-multiplying bacteria.
Figure 6: Development of new antimicrobials through genome hunting.
Figure 7: Killing non-multiplying bacteria with one-dose therapy.
Figure 8: New sensitivity tests for clinically latent bacteria: MSC and MDC.

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Authors and Affiliations

  1. Department of Medical Microbiology, St George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE, UK

    Anthony Coates & Yanmin Hu

  2. BioTherapies Ltd, Octagon House, Fir Road, Bramhall, Stockport, SK7 2NP, Cheshire, UK

    Anthony Coates & Yanmin Hu

  3. Biosyn, Inc., Building 13, 1800 Byberry Road, Huntingdon Valley, 19006, Pennsylvania, USA

    Richard Bax

  4. Sackler Institute of Pulmonary Pharmacology, GKT School of Biomedical Sciences, King's College, London, SE1 9RT, London, UK

    Clive Page

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Glossary

ANTIMICROBIAL AGENTS

This term includes antibiotics and chemically derived agents.

RESISTANCE TO ANTIMICROBIAL AGENTS

A microbe that survives, for example, treatment with an antimicrobial agent (at or above the MIC) by altering its genome is resistant to that drug. The progeny of that microbe will also be genetically resistant to the agent.

LATENT

Existing but hidden.

CLINICALLY LATENT BACTERIA

A hidden infection with a pathogen that might involve microbial growth, which is balanced by host control mechanisms, so that the infection remains below the threshold of infectious disease expression. Conversely, the pathogen might be non-replicating. It is not usually possible to distinguish between replicating and non-replicating bacteria in vivo.

ANTIBIOTICS

Naturally derived antimicrobial agents.

INFECTION

The multiplication and growth of pathogens in host tissues or on host epithelia.

GROWTH

Accumulation of biomass.

MULTIPLICATION

Genomic growth and segregation into a new self-propagating unit.

SURVIVAL

Maintenance of viability.

DORMANCY

A reversible state of low metabolic activity in a unit that maintains viability. The non-culturable form of Micrococcus luteus is an example of the dormant state.

RESUSCITATION

Transition from a temporary state in which the specified unit had lost the capacity to multiply, to a state in which multiplication can take place.

INFECTIOUS DISEASE

When an infection causes a disease, such as bacterial pneumonia. It is usually associated with the potential to transmit the causative pathogen to other people.

STATIONARY PHASE

This is a growth phase that is slow or non-multiplying and is observed in vitro. Stationary phase bacteria are widely used in in vitro models.

VIABLE

Capable of multiplication.

TOLERANCE TO ANTIMICROBIAL AGENT

A microbe that survives treatment with an antimicrobial agent (at or above the minimum inhibitory concentration (MIC)) without altering its genome is said to be tolerant. For example, multiplying log-phase Mycobacterium tuberculosis is killed by sub-μg per ml concentrations of rifampicin. However, when the growth of the organism slows, it can survive. In other words, it tolerates higher concentrations of rifampicin; in certain situations one thousand times the MIC. The survivors, or persisters, become highly sensitive to rifampicin again when they re-enter the log-phase.

PERSISTENCE

The continued viability of a pathogen after treatment with an antimicrobial agent. The bacteria might be clinically latent, or might cause an infectious disease.

CULTURABLE

Capable of detectable multiplication.

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Coates, A., Hu, Y., Bax, R. et al. The future challenges facing the development of new antimicrobial drugs. Nat Rev Drug Discov 1, 895–910 (2002). https://doi.org/10.1038/nrd940

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