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Title: Differential daptomycin resistance development in Staphylococcus aureus strains with active and mutated gra regulatory systems
Authors: Müller, Anna
Grein, Fabian
Otto, Andreas
Gries, Kathrin
Orlov, Dmitriy
Girard, Myriam
Sher, Xinwei
Shamova, Olga
Roemer, Terry
François, Patrice
Becher, Dörte
Schneider, Tanja
Sahl, Hans-Georg
Zarubaev, Vladimir V. 
Keywords: Antibiotic resistance;Daptomycin;GraRS regulatory system;Serial passaging
Issue Date: Apr-2018
Publisher: Elsevier
Journal: International Journal of Medical Microbiology 
Abstract: 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.
ISSN: 1438-4221
DOI: 10.1016/j.ijmm.2017.12.002
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