title: Regulatory Mutations Impacting Antibiotic Susceptibility in an Established Staphylococcus aureus Biofilm.
abstract: We previously determined the extent to which mutations of different Staphylococcus aureus regulatory loci impact biofilm formation as assessed under in vitro conditions. Here we extend these studies to determine the extent to which those regulatory loci that had the greatest effect on biofilm formation also impact antibiotic susceptibility. The experiments were done under in vitro and in vivo conditions using two clinical isolates of S. aureus (LAC and UAMS-1) and two functionally diverse antibiotics (daptomycin and ceftaroline). Mutation of the staphylococcal accessory regulator (sarA) or sigB was found to significantly increase susceptibilities to both antibiotics and in both strains in a manner that could not be explained by changes in the MICs. The impact of a mutation in sarA was comparable to that of a mutation in sigB and greater than the impact observed with any other mutant. These results suggest that therapeutic strategies targeting sarA and/or sigB have the greatest potential to facilitate the ability to overcome the intrinsic antibiotic resistance that defines S. aureus biofilm-associated infections.
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Danielle N
authors.identifier: http://orcid.org/0000-0002-9106-3386
authors.initials: DN
authors.lastname: Atwood
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Beenken
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lantz
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Meeker
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Lynn
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Weston B
authors.initials: WB
authors.lastname: Mills
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Horace J
authors.initials: HJ
authors.lastname: Spencer
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA smeltzermarks@uams.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Smeltzer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D055499:Catheter-Related Infections / Q000188:drug therapy / Q000382:microbiology; D057785:Catheters / Q000382:microbiology; D002511:Cephalosporins / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D012808:Sigma Factor / Q000235:genetics*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D017576:Daptomycin; D012808:Sigma Factor; D000097583:Ceftaroline; C492107:SarA protein, Staphylococcus aureus; C079011:SigB protein, Bacteria
references.citation: J Bacteriol. 2011 Jun;193(12):2948-58
references.pmid: 21478342
references.citation: Mol Ecol Resour. 2012 Nov;12(6):1068-78
references.pmid: 22934781
references.citation: PLoS Pathog. 2015 Apr;11(4):e1004870
references.pmid: 25923704
references.citation: Microbiologyopen. 2015 Jun;4(3):436-51
references.pmid: 25810138
references.citation: J Bacteriol. 2001 Sep;183(17):5171-9
references.pmid: 11489871
references.citation: Antimicrob Agents Chemother. 2009 Oct;53(10):4096-102
references.pmid: 19651914
references.citation: J Bacteriol. 2005 Jan;187(2):576-92
references.pmid: 15629929
references.citation: Microbiology. 2006 Oct;152(Pt 10):3075-90
references.pmid: 17005987
references.citation: Curr Top Microbiol Immunol. 2008;322:107-31
references.pmid: 18453274
references.citation: Antimicrob Agents Chemother. 2009 Jun;53(6):2475-82
references.pmid: 19289527
references.citation: Mol Microbiol. 2003 May;48(4):1075-87
references.pmid: 12753197