Mechanisms of Resistance to Lipopeptide Antibiotics in Gram-Positive Pathogens




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Daptomycin (DAP) and surotomycin (SUR) are lipopeptide antibiotics with bactericidal activity against Gram-positive pathogens. Their addition into clinicians’ antibiotic repertoire was an important step in combating increasing numbers of multi-drug resistant (MDR) infectious agents. DAP has been shown to have potent activity against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). However, resistance to DAP has emerged over the last 20 years. Resistance to moderate concentrations of DAP (4-32 µg/mL) has been demonstrated in Gram-positive model organisms such as S. aureus and B. subtilis. This resistance is normally a step-wise process involving multiple genes working together. Recently, studies on the viridans group streptococci (VGS) and their response to DAP have demonstrated that rapid mechanisms of resistance can develop in these opportunistic pathogens. Specifically, VGS exposed to DAP overnight are capable of acquiring resistance to high concentrations of DAP (> 256 µg/mL). SUR has been approved to treat C. difficile associated diarrhea (CDAD), a disease with a high rate of recurrence which places a large economic burden on the healthcare industry. SUR has been shown to be more effective than the current CDAD treatment regimen of vancomycin. However, like DAP, resistance to SUR has also been observed in laboratory and clinical settings. In my research, I analyzed the genomes of DAP-resistant VGS S. mitis and S. oralis, as well as SUR-resistant C. difficile and E. faecium. Using comparative genomics, I identified polymorphisms occurring in resistant populations. Briefly, mutations identified in SUR-resistant C. difficile and E. faecium are similar to mutations previously identified in studies of DAP resistance, suggesting that these two lipopeptides share a common mechanism of action. Additionally, I identified a mutation in a single gene (cdsA) within the VGS that conferred resistance to DAP. To date, mutations in this gene have not been seen, as cdsA is considered to be essential for bacterial growth. cdsA encodes the enzyme phosphatidate cytidylyltransferase (CdsA), which is responsible for the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG). CDP-DAG is the common precursor for the synthesis of all major phospholipids found in bacterial membranes. Using lipidomics, I confirm that these cdsA mutations result in a loss-of-function phenotype, as demonstrated by the accumulation of PA in the membranes of S. mitis and S. oralis and the depletion of the lipids phosphatidylglycerol and cardiolipin. Taken together, my research provides critical insight into the mechanisms of resistance to the clinically relevant antibiotics DAP and SUR, as well as providing evidence that S. mitis and S. oralis share a unique physiology that allows them to survive CdsA loss-of-function mutations.



Drug resistance, Gram-positive bacteria, Streptococcus, Comparative genomics, Phospholipids