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Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action

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Abstract

Efforts to reduce the global burden of bacterial disease and contend with escalating bacterial resistance are spurring innovation in antibacterial drug and biocide development and related technologies such as photodynamic therapy and photochemical disinfection. Elucidation of the mechanism of action of these new agents and processes can greatly facilitate their development, but it is a complex endeavour. One strategy that has been popular for many years, and which is garnering increasing interest due to recent technological advances in microscopy and a deeper understanding of the molecular events involved, is the examination of treated bacteria for changes to their morphology and ultrastructure. In this review, we take a critical look at this approach. Variables affecting antibacterial-induced alterations are discussed first. These include characteristics of the test organism (e.g. cell wall structure) and incubation conditions (e.g. growth medium osmolarity). The main body of the review then describes the different alterations that can occur. Micrographs depicting these alterations are presented, together with information on agents that induce the change, and the sequence of molecular events that lead to the change. We close by highlighting those morphological and ultrastructural changes which are consistently induced by agents sharing the same mechanism (e.g. spheroplast formation by peptidoglycan synthesis inhibitors) and explaining how changes that are induced by multiple antibacterial classes (e.g. filamentation by DNA synthesis inhibitors, FtsZ disruptors, and other types of agent) can still yield useful mechanistic information. Lastly, recommendations are made regarding future study design and execution.

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Fig. 1

Images from [97] by permission of Antimicrobial Agents and Chemotherapy (ASM)

Fig. 2

Images from [101] by permission of Innate Immunity (SAGE Publications)

Fig. 3

Images a and b from [67] by permission of Antimicrobial Agents and Chemotherapy (ASM), and c and d from [133] by permission of the Journal of Bacteriology (ASM)

Fig. 4

Images from [125] by permission of Antimicrobial Agents and Chemotherapy (ASM)

Fig. 5

Images a and b from [101] by permission of Innate Immunity (SAGE Publications), and images c and d from [169] by permission of the Journal of Bacteriology (ASM)

Fig. 6

Images a and b from [171] and images c and d from [83], all by permission of the Journal of Medical Microbiology (MicroSoc)

Fig. 7

Images a and b from [171] by permission of the Journal of Medical Microbiology (MicroSoc), and images c and d from [180] by permission of the Journal of Bacteriology (ASM)

Fig. 8

Images from [155] by permission of Reviews of Infectious Diseases (Oxford University Press)

Fig. 9

Images from [195] by permission of the Journal of Medical Microbiology (MicroSoc)

Fig. 10

Images from [195] by permission of the Journal of Medical Microbiology (MicroSoc)

Fig. 11

Images from [202] by permission of Proceedings of the Society for Experimental Biology and Medicine (SAGE Publications)

Fig. 12

Images from [203] by permission of the Journal of Antimicrobial Chemotherapy (Oxford University Press)

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Acknowledgments

We are very grateful to those authors who helped source the more-difficult-to-find journal articles used in this review, in particular Professors Francesco Castelli, Magnús Gottfreðsson, Giovanni Longo, Vsevolod L. Popov, R. Michael E. Richards, Brian G. Spratt, and Alexander Tomasz. We are also extremely grateful to Colin MacLean and the Interlibrary loan staff at the Robert Gordon University for their assistance with this project, and to Dr. Helen Vosper for constructive comments during drafting of the manuscript. Our apologies to authors whose work could not be included due to space restrictions.

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  1. Faculty of Medicine, Mahasarakham University, Khamriang, Kantarawichai, Maha Sarakham, 44150, Thailand

    T. P. Tim Cushnie

  2. School of Pharmacy and Life Sciences, Robert Gordon University, Sir Ian Wood Building, Garthdee Road, Aberdeen, AB10 7GJ, UK

    Noëlle H. O’Driscoll & Andrew J. Lamb

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Cushnie, T.P.T., O’Driscoll, N.H. & Lamb, A.J. Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action. Cell. Mol. Life Sci. 73, 4471–4492 (2016). https://doi.org/10.1007/s00018-016-2302-2

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