The Global Regulon<i>sarA</i>Regulates β-Lactam Antibiotic Resistance in Methicillin-Resistant<i>Staphylococcus aureus</i>In Vitro and in Endovascular Infections

Li, Liang; Cheung, Ambrose L.; Bayer, Arnold S.; Chen, Liang; Abdelhady, Wessam; Kreiswirth, Barry N.; Yeaman, Michael R.; Xiong, Yan Q.

doi:10.1093/infdis/jiw386

Cited by 45 publications

(75 citation statements)

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“…The mecA locus encodes penicillin-binding protein 2a (PBP2a) that confers β-lactam resistance in MRSA strains (24). In addition, recent studies have demonstrated that the global virulence gene regulator, sarA, can also modulate β-lactam resistance via both mecA- dependent and mecA -independent mechanisms (23). To investigate the influence of NaHCO 3 exposure on mecA and sarA gene expression, RNA was extracted from cells grown in media with and without NaHCO 3 in the absence or presence of ½ MIC of oxacillin (to maximally induce mecA expression).…”

Section: Resultsmentioning

confidence: 99%

“…It is unclear, however, if NaHCO 3 has a direct impact on mecA expression, or if altered mecA gene expression is mediated through repression of sarA or other global regulons. Recent studies have shown that deletion of sarA and sigB can reduce mecA expression (23); therefore NaHCO 3 may be altering mecA expression directly and/or through one or both of these global regulatory pathways. In addition, we observed the mecA and sarA expression levels were reduced by NaHCO 3 exposures, in both the presence or absence of oxacillin induction ( Figs 5A;B ).…”

Section: Discussionmentioning

confidence: 99%

“…These prototypical strains encompass the range of clonal complex, agr and SCCmec genotypes that are in current worldwide clinical circulation. In addition, several of these strains have been previously used in experimental studies of virulence, pathogenesis and antimicrobial responsiveness (MW2; COL; and MRSA 11/11) (5, 23, 53, 66). In experimental IE studies, we also included the well-known MSSA strain, ATCC25923, as a control.…”

Section: Methodsmentioning

confidence: 99%

“…If verified in larger MRSA screening studies, these novel findings may potentially prompt modifications of AST for MRSA; this, in turn, could potentially guide new treatment algorithms for selected MRSA infections with β-lactam agents such as cefazolin and anti-staphylococcal penicilins. Finally, mechanistically, NaHCO 3 -responsiveness correlated with the capacity of this molecule to suppress at least two key regulatory pathways intimately involved in the MRSA phenotype: mecA -PBP2a and sarA (5, 23, 24).…”

Section: Introductionmentioning

confidence: 95%

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Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Ersoy

Abdelhady

et al. 2019

Preprint

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23Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) 24 are a major healthcare concern, especially infective endocarditis (IE). Standard 25 antimicrobial susceptibility testing (AST) defines most MRSA strains as 'resistant' to β-26 lactams, often leading to use of costly and/or toxic treatment regimens. In this 27 investigation, five prototype MRSA strains, representing the range of genotypes in 28 current clinical circulation, were studied. We identified two distinct MRSA phenotypes 29 upon AST using standard media, with or without sodium bicarbonate (NaHCO 3 ) 30 supplementation: one highly susceptible to the anti-staphylococcal β-lactams, oxacillin 31 and cefazolin ('NaHCO 3 -responsive') and one resistant to such agents ('NaHCO 3 -32 nonresponsive'). These phenotypes accurately predicted clearance profiles of MRSA 33 from target tissues in experimental MRSA IE treated with each β-lactam. 34Mechanistically, NaHCO 3 reduced expression of two key genes involved in the MRSA 35 phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 36 (PBP) 2a (that mediates methicillin resistance), in NaHCO 3 -responsive (but not in 37 NaHCO 3 -nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically 38 killed NaHCO 3 -responsive strains in the presence of the host defense antimicrobial 39 peptide (LL-37) in NaHCO 3 -supplemented media. These findings suggest that AST of 40 MRSA strains in NaHCO 3 -containing media may potentially identify infections caused by 41 NaHCO 3 -responsive strains that are appropriate for β-lactam therapy. 42 Word count: 199 43 44 3 Keywords: 45 Methicillin-resistant Staphylococcus aureus (MRSA); Infective Endocarditis (IE) 46 Antimicrobial Susceptibility Testing (AST); Beta-lactams (β-lactams); 47 50 Staphylococcus aureus is a major bloodstream pathogen in both community-51 acquired and nosocomially-acquired scenarios, and is the leading cause of infective 52 endocarditis (IE) in the industrialized world (1). Compounding the danger of S. aureus 53 bloodstream infections (BSIs) is the steady rise of methicillin-resistant Staphylococcus 54 aureus (MRSA) strains in many geographic regions in the US (2). MRSA is a serious 55 infectious threat, causing more than 15,000 deaths in the U.S. each year (3). 56 MRSA have high minimal inhibitory concentrations (MICs) that are above Clinical 57 Laboratory Standards Institute [CLSI] resistance breakpoints for most conventional β-58 lactam antibiotics, such as oxacillin, on standard antimicrobial susceptibility testing 59 (AST) media. This finding implies a lack of efficacy of these agents in treating MRSA 60 infections, as confirmed in selected experimental IE studies (4-6). Treatment options for 61 MRSA are generally limited to costlier and/or more toxic drugs such as vancomycin, 62 daptomycin, lipoglycopeptides, and fifth generation cephalosporins, such as ceftaroline 63 (7-9). Additionally, great expense and effort have gone into development of such newer 64 anti-MRSA drug...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Ersoy

Abdelhady

et al. 2019

Preprint

Self Cite

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“…The suppression of ABC transporters was another mechanism of anti-biofilm by 12C-Rha since nine proteins (OpuC, CycB, PstC, PhnC, ZnuA, MtsA, MtsB, HrtA and BraD) mapped to ABC transporters were downregulated. Thus, related substrates such as osmoprotectant, arabinogalactan oligomer/ maltooligosaccharide, phosphate, phosphonate, iron/zinc/ manganese/copper, hemin and bacitracin could not be transported properly in biofilm cells, causing the disruption of S. aureus biofilms [28]. Moreover, the function of ZnuA and MtsA that is directly related with iron transportation should be emphasized because iron is important for biofilm development [29].…”

Section: Discussionmentioning

confidence: 99%

Alkyl rhamnosides, a series of amphiphilic materials exerting broad-spectrum anti-biofilm activity against pathogenic bacteria via multiple mechanisms

Peng

Hou

Zhang

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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As novel amphiphilic materials, six uncharged alkyl rhamnosides incorporating various alkyl chain and one rhamnose amine quaternary ammonium salt were successfully synthesized in this study. Their amphiphilic properties (HLB and CMC), antimicrobial and anti-biofilm activity against S. aureus and P. aeruginosa were investigated. Differentially regulated proteins and pathways were identified by comparative proteomics research to first give a sight on how alkyl rhamnosides performed the anti-biofilm activity at protein and pathway levels. Among the uncharged alkyl rhamnosides, dodecyl rhamnoside and octyl rhamnoside showed the best antimicrobial and anti-biofilm ability against S. aureus and against P. aeruginosa, respectively. Interestingly, the relationships between amphiphilic properties or MIC with anti-biofilm activity were first established. Uncharged alkyl rhamnoside with an optimized HLB value of 5.0 had both the strongest antibacterial and anti-biofilm activity against S. aureus, and MIC was the maximum biofilm inhibitory concentration for all alkyl rhamnosides. Alkyl rhamnosides have a significant overall regulatory effect on the proteomics and pathways of bacterial biofilms, including energy production, substrates transportation, signal transduction, key molecules balance, and so on. These amphiphilic materials have a great potential to be used as additives in pharmaceutic, cosmetic, food industry, hospital and in other non-medical fields.

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Bacterial Persistence in Biofilms and Antibiotics

Jolivet‐Gougeon

Bonnaure‐Mallet

2019

Antibiotic Drug Resistance

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The Global RegulonsarARegulates β-Lactam Antibiotic Resistance in Methicillin-ResistantStaphylococcus aureusIn Vitro and in Endovascular Infections

Cited by 45 publications

References 51 publications

Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

Alkyl rhamnosides, a series of amphiphilic materials exerting broad-spectrum anti-biofilm activity against pathogenic bacteria via multiple mechanisms

Bacterial Persistence in Biofilms and Antibiotics

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