Jeff has spent his 35 year research career addressing fundamental questions about the structure and function of bacterial cells. He has made important contributions to our understanding of the molecular biology of endospore formation in Bacillus subtilis and more recently of chromosome replication and segregation, cell division and cell morphogenesis. He was a pioneer in the application of digital fluorescence imaging methods to bacteria.
Jeff has also been actively involved in the exploitation of basic science, founding two antibiotic discovery spin out companies: Prolysis Ltd (now part of Aviragen Therapeutics) and Demuris Ltd, spun-out from Newcastle University. His work has been recognized through a number of awards, including: Fellowship of the Royal Society, EMBO, the UK Academy of Medical Sciences and the American Academy of Microbiology.
Immune cells can protect bacteria from β-lactam killing by promoting an L-form switch
β-lactam antibiotics prevent cell wall assembly leading to explosive cell death under classical microbiological culture conditions. However, under osmoprotective conditions lysis is largely prevented, though the cells are prevented from growing and die, possibly through other pathways such as oxidative damage and futile cycling of the cell wall precursor pathway. Historically, β-lactam antibiotic treatments have been used to promote the formation and stabilization of wall free bacteria called L-forms, which have been postulated to provide a route to antibiotic tolerance in clinical situations. We recently showed that the L-form switch can be efficiently driven by inhibition of cell wall precursor synthesis but not by β-lactam treatment. We have no found that β-lactams fail to induce L-form switching because autolytic enzymes responsible for escape of the cell protoplast from the parent walled cell are inhibited in response to these antibiotics. We show that addition of exogenous lytic enzymes, such as lysozyme, enables L-form escape and protects from cell killing by the antibiotic. We go on to show that the L-form transition can be initiated by the interaction of bacteria with lysozyme producing macrophages or larvae of Galleria mellonella. In macrophages, at least, we show that bacteria can be protected from β-lactam killing, apparently by conversion into an L-form state. As well as highlighting remarkable interactions between lysozyme and β-lactams the results highlight the potential importance of L-forms in antibiotic evasion and recurrent infection. Importantly, L-forms differ from other forms of “persister” in being capable of continued growth and division during antibiotic treatment.
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