Bacterial lipocalins: Novel role in bacterial protection against antibiotic-induced membrane lipid peroxidation

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Research on antibiotic action and resistance has helped elucidate fundamental biochemical and regulatory pathways in bacteria and fungi operating within the microbial cells. However, whether bacteria produce molecules that interfere with antibiotics before they reach cells has been overlooked. We discovered a previously unrecognized mode of bacterial antibiotic resistance operating in the extracellular space that depends on molecules produced and released by bacteria in response to sublethal antibiotic concentrations. This adaptive mechanism protects less resistant bacterial cells of the same or different species from killing by antibiotics. The molecules involved are putrescine, a polyamine, and secreted lipocalin proteins, which are highly conserved in bacteria. We also discovered that lipocalins are part of a previously ignored mechanism to protect cell membranes from lipid peroxidation. Peroxidation occurs as a consequence of environmental stress including bacterial exposure to near-lethal antibiotic concentrations, cold, and inflammation. Lipid peroxidation ends up with the destruction of membrane lipids and their conversion into highly toxic forms which in turn can oxidise and destroy cellular proteins and the genetic material. This proposal is on fundamental microbiology research combining molecular microbiology, biochemistry, and infection models to elucidate the role of a conserved family of bacterial lipocalins in bacterial cell physiology and antibiotic resistance. Our long-term goals are to establish the function of lipocalins by elucidating their mechanism and physiological roles in bacterial cells, and to utilise this information to gain proof of principle that new molecules can be designed to help prevent extracellular bacterial scavenging of antibiotics, and more importantly accelerate peroxidation leading to bacterial death, thus providing a potentially new solution to combat antibiotic resistance.