Complexity matters: polymyxin antibiotics and the bacterial cell envelope

Abstract

The rise of antibiotic resistance in bacteria, such as Escherichia coli, poses a significant threat to global public health. One class of antibiotics, the polymyxins, are seeing a surge in use as a treatment against infection by multi-drug resistant Gram-negative bacteria due to their highly potent antimicrobial activity. Whilst these drugs are effective in their purpose, reports of severe nephro- and neurotoxicity have limited their use to only the most serious clinical cases in which all other treatment options have failed. This toxicity, in combination with recent reports of polymyxin resistance observed within certain bacterial strains, provides an immediate motivation to gain a mechanistic understanding of how these drugs perform each stage of their antimicrobial function so as to better inform the development of novel therapeutics. To do so in a rational manner demands a thorough understanding of the behaviour of the polymyxins within the region of the bacterial cell in which they perform their function.

To this end, the work presented in this thesis uses the computational technique of molecular dynamics for the purpose of simulating polymyxin antibiotics within the E. coli cell envelope. The nature of the molecular interactions between the polymyxins and the various structures of the cell envelope are studied in depth. Through varying the composition of the proteins, osmolytes and ions within the periplasm it is shown that the duration and biochemical nature of polymyxin binding with the cell wall and Braun’s lipoprotein are modulated by interactions with the constituents of the surrounding environment.

The energetics and conformational dynamics of polymyxin permeation into the inner membrane are also investigated using a variety of enhanced sampling methods. It is shown that the polymyxins spontaneously insert into the headgroup region of the inner membrane through the adoption of a folded amphipathic conformation. The similarities of this mechanism to the insertion of other antimicrobial and designed peptides into lipid bilayers, reported in literature, are also discussed.

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Identifiers

ORCID for Iain Peter Shand Smith: orcid.org/0000-0002-1562-3361

ORCID for Syma Khalid: orcid.org/0000-0002-3694-5044

ORCID for Jeremy Frey: orcid.org/0000-0003-0842-4302

ORCID for Ian Hawke: orcid.org/0000-0003-4805-0309

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