Abstract
Proteus mirabilis is a common pathogen of the catheterised urinary tract and often described as intrinsically resistant to the biocide chlorhexidine (CHD). Here we demonstrate that de-repression of the smvA efflux system has occurred in clinical isolates of P. mirabilis and reduces susceptibility to CHD and other cationic biocides. Compared to other isolates examined, P. mirabilis RS47 exhibited a significantly higher CHD MIC (≥512 μg/ml) and significantly greater expression of smvA. Comparison of the RS47 smvA and cognate smvR repressor with sequences from other isolates, indicated that RS47 encodes an inactivated smvR. Complementation of RS47 with a functional smvR from isolate RS50a (which exhibited the lowest smvA expression and lowest CHD MIC) reduced smvA expression by ∼59-fold, and markedly lowered the MIC of CHD and other cationic biocides. Although complementation of RS47 did not reduce MICs to concentrations observed in isolate RS50a, the significantly lower polymyxin B MIC of RS50a indicated that differences in LPS structure are also a factor in P. mirabilis CHD susceptibility. To determine if exposure to CHD can select for mutations in smvR, clinical isolates with the lowest CHD MICs were adapted to grow at increasing concentrations of CHD up to 512 μg/ml. Analysis of the smvR in adapted populations indicated that mutations predicted to inactivate smvR occurred following CHD exposure in some isolates. Collectively, our data show that smvA de-repression contributes to reduced biocide susceptibility in P. mirabilis, but differences in LPS structure between strains are also likely to be an important factor.
Highlights
Biocides play an important role in infection control and are often used to remove microbes from equipment, surfaces, and skin prior to medical procedures [1,2,3]
Examples of applications include the prevention of ventilator-associated pneumonia, the decontamination of skin at puncture or incision sites, control of wound infections, hard surface disinfection, decolonization of patients carrying opportunistic pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), and prevention of infections related to central venous catheterization [5, 7, 8, 13,14,15,16]
The SmvA efflux pump is a member of the major facilitator superfamiliy (MFS) of transporters and was first described in Salmonella enterica serovar Typhimurium, where it was associated with efflux of quaternary ammonium compounds (QACs) and methyl-viologen resistance [20, 21]
Summary
Biocides play an important role in infection control and are often used to remove microbes from equipment, surfaces, and skin prior to medical procedures [1,2,3]. The rising incidence of multidrug resistance in nosocomial pathogens has further magnified the clinical value of biocides, and there is increasing reliance on these antimicrobials to reduce antibiotic usage through more effective infection control strategies [1, 4,5,6]. Despite their clinical significance, biocides are subject to far fewer regulations on their use than therapeutic agents, such as antibiotics [2]. To date, we have only observed mutations in smvR that lead to reduced CHD susceptibility in K. pneumoniae and other species in laboratory experiments, and the clinical relevance of this biocide resistance mechanism remains unclear
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