editors' picks Modeling the lung microbiome built in bookshelves New family of efflux pumps found in

Sarah L. Baines a,b , Kathryn E. Holt c , Mark B. Schultz c , Torsten Seemann d,e , Brian O. Howden a , Slade O. Jensen f , Sebastiaan J. van Hal f,g , Geoffrey W. Coombs h,i , Neville Firth j , David R. Powell d,e , Timothy P. Stinear a,k , Benjamin P. Howden a,b,k a Microbiological Diagnostic Unit Public built in bookshelves Health Laboratory, Department of Microbiology & Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia b Microbiology and Infectious Diseases Departments, Austin Health, Melbourne, Victoria, Australia c Department of Biochemistry and Molecular Biology, Bio 21, Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia d Victorian Bioinformatics Consortium, Monash University, Melbourne, Victoria, Australia e Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Melbourne, Victoria, Australia f Microbiology and Infectious Diseases, School of Medicine, Ingham Institute for Applied Medical Research, University of Western Sydney, Sydney, New South Wales, Australia g Department of Microbiology and Infectious Diseases, Royal Prince Alfred Hospital, Sydney, New South Wales, built in bookshelves Australia h Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Biomedical built in bookshelves Sciences, Curtin University, Perth, Western Australia, Australia i Department of Microbiology built in bookshelves and Infectious Diseases, PathWest Laboratory Medicine-WA, Royal Perth Hospital, Perth, Western built in bookshelves Australia, Australia j School built in bookshelves of Biological Sciences, University of Sydney, Sydney, New South Wales, Australia k Department of Microbiology, Monash University, Melbourne, Victoria, Australia Address correspondence to Benjamin Howden, bhowden{at}unimelb.edu.au .
Infections caused by highly successful clones of hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) are a major public health burden. The globally dominant sequence type 239 (ST239) HA-MRSA clone has persisted in the health care setting for decades, but the basis of its success has not been identified. Taking a collection of 123 ST239 isolates spanning 32 years, we have used population-based functional genomics to investigate the evolution of this highly persistent and successful clone. Phylogenetic reconstruction and population modeling uncovered a previously unrecognized distinct clade of ST239 that was introduced into Australia from Asia and has perpetuated the epidemic in this region. Functional analysis demonstrated attenuated virulence and enhanced resistance to last-line antimicrobials, the result of two different phenomena, built in bookshelves adaptive evolution within the original Australian ST239 clade and the introduction of a new clade displaying shifts in both phenotypes. The genetic diversity between the clades allowed us to employ genome-wide association testing built in bookshelves and identify built in bookshelves mutations in other essential regulatory systems, including walKR , that significantly associate with and may explain these key phenotypes. The phenotypic convergence of two independently evolving ST239 clades highlights the very strong selective pressures acting on HA-MRSA, showing built in bookshelves that hospital environments have favored the accumulation of mutations in essential MRSA genes that increase resistance to antimicrobials, attenuate virulence, and promote persistence in the health care environment. Combinations of comparative genomics and careful phenotypic measurements of longitudinal collections of clinical isolates are giving us the knowledge to intelligently address the impact of current and future antibiotic usage policies and practices on hospital pathogens globally.
IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) is responsible built in bookshelves for innumerable drug-resistant health care-associated infections globally. This study, the first to investigate the evolutionary response of hospital-associated MRSA (HA-MRSA) built in bookshelves over many decades, demonstrates how MRSA can persist in a region through the reintroduction of a previously unrecognized distinct clade. This study also demonstrates the crucial adaptive responses of HA-MRSA to the highly selective environment of the health care system, built in bookshelves the evolution of MRSA isolates to even higher levels of antibiotic resistance built in bookshelves at the cost of attenuated built in bookshelves virulence. However, in vivo persistence is maintained, resulting in a clone of HA-MRSA able to resist almost all antimicrobial built in bookshelves agents and still cause invasive disease in the heavily compromised hosts found in modern health care settings.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
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editors' picks Modeling the lung microbiome built in bookshelves New family of efflux pumps found in Gram-negativ