Defining mechanisms of antiseptic tolerance against skin microbiota

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Antiseptics are critical to prevention of infection in humans and animals as bacteria normally found on the skin are the major causes of infections when they gain access to the blood via breakage of the skin barrier or via catheters inserted for various medical reasons. In particular a group of staphylococci (related to MRSA) known as 'coagulase negative staphylococcus (CoNS)' live on skin and cause serious infections in animals and humans, particularly premature babies. Current measures to prevent infection rely on the use of antiseptics to remove pathogens from the skin and hence stop them causing infection. Two major antiseptics are used clinically:chlorhexidine and octenidine, with chlorhexidine also being widely used in animals. Together, these agents are crucial in preventing infections. Recently there have been multiple reports documenting the identification of CoNS which are unusually tolerant to antiseptics prompting worries that they may become resistant to antisepsis which would result in increased infection risk to humans and animals.Despite the widespread use of chlorhexidine and octenidine, little is known about how they work and how bacteria could develop resistance to them. The study proposed here will study how these agents work and explore whether antiseptic resistance can occur and if so whether mutant bacteria also become cross-resistant to antibiotics as a result. We have recently assembled a collection of 1250 CoNS from the skin of babies from two neonatal intensive care units. One in the UK where chlorhexidine is used and one in Germany where octenidine is used. We have seen there are clear differences in antiseptic tolerance between the two units. In this study we will decode the genomes of all the strains we have collected and compare this information with antiseptic susceptibility. This will allow us to identify any genetic changes that cause antiseptic tolerance in the isolates. We will combine this approach with laboratory studies where we will expose selected isolates to each antiseptic and study how they become tolerant. Importantly, we have developed a human skin model we can use to do this which will be a realistic proxy for use in the real world. Again, we will sequence the genomes of any resistant mutants. Together this genetic analysis of resistant isolates and mutants will help us understand the genes involved in antiseptic resistance. We will also see if exposing isolates to the antiseptics makes them change their antibiotic resistance which could result in harder to treat infections.The applicants have a strong background in studying disinfectants, bacterial genomics and skin responses to infection and we will use those skills here. The data we produce will be used and shared with clinical and veterinary colleagues to inform how best to use antiseptics in animals and humans with a focus on premature babies. We will be able to assess if there is a difference in the risk of bacteria becoming resistant to either of the two major antiseptics which can guide best practice. We will also generate useful information about the mechanisms by which both agents work which will help development of new antiseptics in future.