Direct and indirect impacts of polymyxin B1 on gram-negative bacteria and their membranes: a computational study

Abstract

Polymyxins are currently used as a ‘last-resort’ antibiotic against multidrug-resistant bacteria, however, there has been a recent increase in bacterial resistance to polymyxins. If this becomes more prevalent, it could lead to an era in which antibiotics are no longer effective. To prevent this, it is necessary to improve understanding of the mechanism of action of polymyxins, so new antibiotics could be developed, as well as to improve understanding of how resistance occurs. Molecular dynamics simulations enable study of complex systems, such as the Gram-negative cell envelope, while maintaining high levels of molecular detail. In this thesis, coarse-grained and atomistic simulations were used to study the direct and indirect impacts of polymyxins. In the first chapter, multiscale molecular dynamics simulations were used to determine the interactions made by polymyxin B1 with a complex Gram-negative inner membrane model containing phospholipids, small quantities of lipopolysaccharide and inner membrane proteins. This study showed that LPS and, perhaps more surprisingly, membrane proteins had an impact on polymyxin behaviour within the inner membrane. In the second chapter, atomistic simulations were used to systematically investigate the impact of lipid A phosphoethanolamine modification (which is commonly associated with polymyxin resistance) on outer membrane model properties. It was found that addition of a single phosphoethanolamine moiety to hexa-or hepta-acylated A. baumannii lipid A resulted in the outer membrane becoming more impenetrable in both the headgroup and tail regions. Finally, atomistic molecular dynamics simulations were used to study the TLR4 modulating properties of various (phosphoethanolamine-modified) A. baumannii lipid A chemotypes, revealing that many of the lipid A chemotypes displayed behaviour indicative of weak agonism (relative to E. coli lipid A). Interestingly, the addition of PEtN to various base lipids (hexa-acylated, hepta-acylated, hepta-acylated + PEtN) resulted in different behaviour, which was also dependent on the binding orientation.

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

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