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  • Review Article
  • Published:

Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections

Nature Reviews Microbiology volume 9, pages 62–75 (2011)Cite this article

Subjects

Key Points

  • When bacteria become quiescent (that is, slow growing or non-growing), they can avoid being killed by bactericidal antibiotics. This phenomenon extends the period of morbidity experienced by the patient and necessitates prolonged antibiotic treatment to achieve a cure.

  • The effects of such bacteria are evident from several infections that typically contain these organisms, such as biofilm diseases, osteomyeletis and tuberculosis granuloma.

  • In the first decade of the new millenium, the discovery and development of antibiotics that target the function of the membrane have provided new paradigms with which to combat persisting bacteria.

  • In one approach, agents disorganize the structure and function of the membrane bilayer, causing subsequent multiple antibacterial effects in cells. Many of these membrane-active agents are reported to kill bacterial biofilms.

  • Moreover, agents that inhibit the function of bacterial respiratory and redox enzymes, thereby causing membrane depolarization and energy depletion, have been shown to kill dormant Mycobacterium tuberculosis.

  • The effects of membrane-active agents on quiescent cell types arise from the fact that all living bacteria require an intact, functional membrane and all living cells require energy to sustain their viability, even without growth.

  • Our understanding of slow-growing or non-growing bacteria has improved, as well as our knowledge about the mechanisms of membrane-acting agents. There are many opportunities for obtaining new classes of drugs based on our current understanding of the mechanisms behind these antimicrobials, as well as many challenges.

Abstract

Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for treating persistent infections. The clinical applicability of these approaches is exemplified by the efficacy of lipoglycopeptides that damage bacterial membranes and of the diarylquinoline TMC207, which inhibits membrane-bound ATP synthase. Despite some drawbacks, membrane-active agents form an important new means of eradicating recalcitrant, non-growing bacteria.

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Figure 1: A generalized view of the action of agents targeting the bacterial membrane and electron transport chain.
Figure 2: Chemical structures of various membrane-active agents.
Figure 3: Chemical structures of agents that disrupt mycobacterial respiration.

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Acknowledgements

We thank E. Tuomanen and E. Mahrous for critical reading of this manuscript. Funding for this research was provided by the US National Institutes of Health grants R01AI062415 and ARRA 1 R01AI079653, and by the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Biology, University of Texas at Arlington, Arlington, 76019, Texas, USA

    Julian G. Hurdle

  2. Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Julian G. Hurdle & Richard E. Lee

  3. Antimicrobial Research Centre and Institute of Molecular and Cellular Biology, University of Leeds, LS2 9JT, Leeds, UK

    Alex J. O'Neill & Ian Chopra

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Correspondence to Julian G. Hurdle.

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Competing interests

Julian G. Hurdle and Richard E. Lee are patent holders of reutericyclin analogues.

Alex J. O'Neill acknowledges receipt of research funding from Helperby Therapeutics.

Ian Chopra has received research grants from Destiny Pharma for studies on the porphyrin antimicrobials XF70 and XF73, and is also a member of Destiny's scientific advisory board.

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Glossary

Persistent infection

An infection that persists in the host for a prolonged period, characterized by the presence of slow-growing and/or non-growing microorganisms. These cells are not easily removed by the host immune system or by antibiotic treatment. Persistent infections may be asymptomatic, but may relapse into active disease when cells regain logarithmic growth and metabolic activity.

Quiescent

Pertaining to bacteria: a bacterial population comprising various subpopulations of slow-growing and non-growing bacteria.

Slow-growing

Pertaining to bacteria: cells in which division occurs at a significantly slower rate than the rate in logarithmic bacteria. These cells display reduced metabolic activity.

Dormant

Pertaining to bacteria: cells that are not undergoing cell division. Overall, cellular metabolism is reduced more than in slow-growing cells. These cells are described as metabolically inactive and non-growing.

Persisting bacteria

Bacteria that persist in the host and are refractory to the host immune system and to antibiotic treatment.

Persister cells

A small subpopulation of non-growing bacteria that arises during the stationary phase and can survive exposure to bactericidal antibiotics.

Logarithmic phase

The bacterial growth phase of during which cell division occurs 'rapidly' to increase bacterial biomass. These cells are metabolically active.

Nephrotoxicity

Having a toxic effect on the kidneys.

Myotoxicity

Having a toxic effect on the muscles.

Lysosomal lipid storage disorder

A metabolic disorder involving the harmful accumulation of lipids in body cells, resulting from a disruption to the function of the lysosome.

Safety margin

The difference between the dose of a drug that is required to produce the best therapeutic effect and that which produces a toxic effect. A wider margin is most desired for therapy.

Prodrug nitroheterocyclic antibiotic

One of a diverse class of compounds that contain a nitroheterocyclic chemical group which undergoes bioreductive activation by enzymes to generate the active antimicrobial species.

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Hurdle, J., O'Neill, A., Chopra, I. et al. Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9, 62–75 (2011). https://doi.org/10.1038/nrmicro2474

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