TY - JOUR

T1 - Differential daptomycin resistance development in Staphylococcus aureus strains with active and mutated gra regulatory systems

AU - Müller, Anna

AU - Grein, Fabian

AU - Otto, Andreas

AU - Gries, Kathrin

AU - Orlov, Dmitriy

AU - Zarubaev, Vladimir

AU - Girard, Myriam

AU - Sher, Xinwei

AU - Shamova, Olga

AU - Roemer, Terry

AU - François, Patrice

AU - Becher, Dörte

AU - Schneider, Tanja

AU - Sahl, Hans Georg

PY - 2018/4

Y1 - 2018/4

N2 - The first-in-class lipopeptide antibiotic daptomycin (DAP) is highly active against Gram-positive pathogens including ß-lactam and glycopeptide resistant strains. Its molecular mode of action remains enigmatic, since a defined target has not been identified so far and multiple effects, primarily on the cell envelope have been observed. Reduced DAP susceptibility has been described in S. aureus and enterococci after prolonged treatment courses. In line with its pleiotropic antibiotic activities, a unique, defined molecular mechanism of resistance has not emerged, instead non-susceptibility appears often accompanied by alterations in membrane composition and changes in cell wall homeostasis. We compared S. aureus strains HG001 and SG511, which differ primarily in the functionality of the histidine kinase GraS, to evaluate the impact of the GraRS regulatory system on the development of DAP non-susceptibility. After extensive serial passing, both DAPR variants reached a minimal inhibitory concentration of 31 μg/ml and shared some phenotypic characteristics (e.g. thicker cell wall, reduced autolysis). However, based on comprehensive analysis of the underlying genetic, transcriptomic and proteomic changes, we found that both strains took different routes to achieve DAP resistance. Our study highlights the impressive genetic and physiological capacity of S. aureus to counteract pleiotropic activities of cell wall- and membrane-active compounds even when a major cell wall regulatory system is dysfunctional.

AB - The first-in-class lipopeptide antibiotic daptomycin (DAP) is highly active against Gram-positive pathogens including ß-lactam and glycopeptide resistant strains. Its molecular mode of action remains enigmatic, since a defined target has not been identified so far and multiple effects, primarily on the cell envelope have been observed. Reduced DAP susceptibility has been described in S. aureus and enterococci after prolonged treatment courses. In line with its pleiotropic antibiotic activities, a unique, defined molecular mechanism of resistance has not emerged, instead non-susceptibility appears often accompanied by alterations in membrane composition and changes in cell wall homeostasis. We compared S. aureus strains HG001 and SG511, which differ primarily in the functionality of the histidine kinase GraS, to evaluate the impact of the GraRS regulatory system on the development of DAP non-susceptibility. After extensive serial passing, both DAPR variants reached a minimal inhibitory concentration of 31 μg/ml and shared some phenotypic characteristics (e.g. thicker cell wall, reduced autolysis). However, based on comprehensive analysis of the underlying genetic, transcriptomic and proteomic changes, we found that both strains took different routes to achieve DAP resistance. Our study highlights the impressive genetic and physiological capacity of S. aureus to counteract pleiotropic activities of cell wall- and membrane-active compounds even when a major cell wall regulatory system is dysfunctional.

KW - Antibiotic resistance

KW - Daptomycin

KW - GraRS regulatory system

KW - Serial passaging

UR - http://www.scopus.com/inward/record.url?scp=85041659894&partnerID=8YFLogxK

U2 - 10.1016/j.ijmm.2017.12.002

DO - 10.1016/j.ijmm.2017.12.002

M3 - Article

C2 - 29429584

AN - SCOPUS:85041659894

VL - 308

SP - 335

EP - 348

JO - International Journal of Medical Microbiology

JF - International Journal of Medical Microbiology

SN - 1438-4221

IS - 3

ER -