Studies on the Mechanism of Telavancin Decreased Susceptibility in a Laboratory-Derived Mutant

Song, Yang; Lunde, Christopher S.; Benton, Bret M.; Wilkinson, Brian J.

doi:10.1089/mdr.2012.0195

Cited by 14 publications

(15 citation statements)

References 50 publications

(72 reference statements)

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“…In our laboratory, we are interested in the mechanisms of action of and resistance to novel and existing anti-staphylococcal antimicrobials [25–27]. Because much antibiotic work employs Mueller-Hinton (MH) medium, [28] we had occasion to determine the fatty acid composition of a S .…”

Section: Introductionmentioning

confidence: 99%

Growth-Environment Dependent Modulation of Staphylococcus aureus Branched-Chain to Straight-Chain Fatty Acid Ratio and Incorporation of Unsaturated Fatty Acids

et al. 2016

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The fatty acid composition of membrane glycerolipids is a major determinant of Staphylococcus aureus membrane biophysical properties that impacts key factors in cell physiology including susceptibility to membrane active antimicrobials, pathogenesis, and response to environmental stress. The fatty acids of S. aureus are considered to be a mixture of branched-chain fatty acids (BCFAs), which increase membrane fluidity, and straight-chain fatty acids (SCFAs) that decrease it. The balance of BCFAs and SCFAs in USA300 strain JE2 and strain SH1000 was affected considerably by differences in the conventional laboratory medium in which the strains were grown with media such as Mueller-Hinton broth and Luria broth resulting in high BCFAs and low SCFAs, whereas growth in Tryptic Soy Broth and Brain-Heart Infusion broth led to reduction in BCFAs and an increase in SCFAs. Straight-chain unsaturated fatty acids (SCUFAs) were not detected. However, when S. aureus was grown ex vivo in serum, the fatty acid composition was radically different with SCUFAs, which increase membrane fluidity, making up a substantial proportion of the total (<25%) with SCFAs (>37%) and BCFAs (>36%) making up the rest. Staphyloxanthin, an additional major membrane lipid component unique to S. aureus, tended to be greater in content in cells with high BCFAs or SCUFAs. Cells with high staphyloxanthin content had a lower membrane fluidity that was attributed to increased production of staphyloxanthin. S. aureus saves energy and carbon by utilizing host fatty acids for part of its total fatty acids when growing in serum, which may impact biophysical properties and pathogenesis given the role of SCUFAs in virulence. The nutritional environment in which S. aureus is grown in vitro or in vivo in an infection is likely to be a major determinant of membrane fatty acid composition.

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Section: Introductionmentioning

confidence: 99%

Growth-Environment Dependent Modulation of Staphylococcus aureus Branched-Chain to Straight-Chain Fatty Acid Ratio and Incorporation of Unsaturated Fatty Acids

et al. 2016

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“…murE, tagB ) and cell wall surface ( spa, clfB, sdrE ) genes. In the TLV obtained in previous studies by Song Y et al (26)most of the differential expressed genes were also associated to changes in cell envelope. These findings suggest that although TLV is an agent with dual mechanism (cell membrane/cell wall) the compensatory preferential mutational mechanism seems to be in higher degree linked to cell wall (CW).…”

Section: Discussionmentioning

confidence: 61%

Activity of Telavancin against S. aureus isolated from cystic fibrosis patients including those with decreased susceptibility to Ceftaroline

Roch

Varela

Taglialegna

et al. 2018

Preprint

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22Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients 23 confers a worse clinical outcome with increased rate of declined lung function. Telavancin, an 24 approved lipoglycopeptide used to treat infections due to S. aureus has a dual mode of action 25 causing inhibition of the peptidoglycan synthesis and membrane depolarization. CF-associated 26 MRSA infections remain an important problem with no foreseeable decline in prevalence rates. 27 Although telavancin is currently in clinical use for complicated skin infections and hospital-28 acquired pneumonia, the activity against CF-associated S. aureus infections has not been 29 investigated. In this work, we studied the activity of telavancin against CF S. aureus strains 30 collected from diverse geographical CF centers in the USA. We found that telavancin-MIC90 was 31 0.06 g/ml, 8-fold lower than ceftaroline or daptomycin and 25-fold lower than linezolid and 32 vancomycin. We demonstrate that telavancin at serum-free concentrations has rapid bactericidal 33 activity with a decrease of more than 3 log10 CFU/ml during the first 4 to 6 hours of treatment, 34 performing better in this assay than vancomycin and ceftaroline, including S. aureus resistant to 35 ceftaroline. 36Telavancin resistance was infrequent (0.3%), although we found that it can occur in-vitro in both 37 CF-and non-CF S. aureus strains by progressive passages with sub-inhibitory concentrations. 38Genetic analysis of telavancin in-vitro mutants showed gene polymorphisms in cell wall and 39 virulence genes, and increased survival in a Galleria mellonella infection model. Thus, we 40 conclude that telavancin represents a promising therapeutic option for CF infections with potent 41 in-vitro activity and low resistance potential. 42 43 48for β-lactams and can mediate cell wall assembly when the normal staphylococcal PBPs (PBP1 to 49 4) are inactivated by these agents (1). S. aureus is one of the earliest and more prevalent pathogens 50 colonizing respiratory tracts and then causing infection in people with cystic fibrosis (CF). This 51 severe, autosomal recessive disease affects several organs, notably the lungs, predisposing these 52 patients to reduced respiratory function and infections with potentially severe consequences. 53According to recent data from the CF Foundation Patient Registry, the prevalence in USA of 54 MSSA is around 70%, while MRSA is 26%. These values compare to 13% in Europe, 6% in 55 Canada and 3% in Australia (2, 3). Emerging research has demonstrated that MRSA infections 56 have a significant clinical impact on individuals with underlying chronic diseases such as CF, 57 where antibiotic pressure and metabolic adaptions may favor the ability of S. aureus to establish 58 long persistence and resistance (4). Additional mechanisms reported in CF lung and other chronic 59 MRSA infections reduce antibiotic activity including small colonies variant adaptation, biofilm 60 formation and growth under anaerobic conditions, which are associat...

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“…Reported in vitro mutational frequency of resistance against dalbavancin, oritavancin, and telavancin has been remarkably, although not unexpectedly, limited (Arthur et al 1999;Krause et al 2005;Sahm et al 2006;Goldstein et al 2007;Laohavaleeson et al 2007;Kosowska-Shick et al 2009;Song et al 2013). Resistance to vancomycin required 30 years in the clinic to become prevalent and required concomitant acquisition of several exogenous genes.…”

Section: Approved Glycopeptide Antibacterial Drugsmentioning

confidence: 99%

“…Two mutants with telavancin MICs 4 times that of the parental strain (32 mg/mL) were selected from vancomycin-resistant enterococci strains (VanA) used; mutant phenotypes were stable on extended subculture, and no changes were observed in growth properties of isolates with reduced susceptibility to telavancin. Song et al (2013) sought to determine mechanisms of decreased telavancin susceptibility in a laboratory-derived mutant of S. aureus, TlvDSMED1952, and showed extensive changes in the mutant transcriptome compared with the susceptible parent strain, MED1951. Upregulated genes in TlvDSMED1952 included cofactor biosynthesis genes, cell-wall-related genes, fatty acid biosynthesis genes, and stress genes, whereas down-regulated genes included lysine operon biosynthesis genes and lrgB (induced by telavancin in susceptible strains), agr and kdpDE genes, various cell surface protein genes, phenol-soluble modulin genes, several protease genes, and genes involved in anaerobic metabolism.…”

Section: Approved Glycopeptide Antibacterial Drugsmentioning

confidence: 99%

Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance

Zeng

Debabov

Hartsell³

et al. 2016

Cold Spring Harb Perspect Med

140

116

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The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action. Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome- and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates.

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Studies on the Mechanism of Telavancin Decreased Susceptibility in a Laboratory-Derived Mutant

Cited by 14 publications

References 50 publications

Growth-Environment Dependent Modulation of Staphylococcus aureus Branched-Chain to Straight-Chain Fatty Acid Ratio and Incorporation of Unsaturated Fatty Acids

Growth-Environment Dependent Modulation of Staphylococcus aureus Branched-Chain to Straight-Chain Fatty Acid Ratio and Incorporation of Unsaturated Fatty Acids

Activity of Telavancin against S. aureus isolated from cystic fibrosis patients including those with decreased susceptibility to Ceftaroline

Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance

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