Intracellular forms of menadione-dependent small-colony variants of methicillin-resistant Staphylococcus aureus are hypersusceptible to  -lactams in a THP-1 cell model due to cooperation between vacuolar acidic pH and oxidant species

Garcia, Laetitia G.; Lemaire, Sandrine; Kahl, Barbara C.; Becker, Karsten; Proctor, Richard A.; Tulkens, Paul M.; Bambeke, Françoise Van

doi:10.1093/jac/dks325

Cited by 15 publications

(13 citation statements)

References 23 publications

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“…However, intracellular menadione-dependent SCVs were shown to be hypersusceptible to ␤-lactams in a cell culture model based on interoperation of vacuolar acidic pH and oxidant species (194). For a compound of the novel MRSA-active class of cephalosporins, ceftobiprole, MRSA-SCVs showed equal or slightly increased MIC values (186).…”

Section: Influence Of Scv Phenotype On Antibiotic Susceptibilitiesmentioning

confidence: 99%

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

2016

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SUMMARYSmall colony variants (SCVs) were first described more than 100 years ago forStaphylococcus aureusand various coagulase-negative staphylococci. Two decades ago, an association between chronic staphylococcal infections and the presence of SCVs was observed. Since then, many clinical studies and observations have been published which tie recurrent, persistent staphylococcal infections, including device-associated infections, bone and tissue infections, and airway infections of cystic fibrosis patients, to this special phenotype. By their intracellular lifestyle, SCVs exhibit so-called phenotypic (or functional) resistance beyond the classical resistance mechanisms, and they can often be retrieved from therapy-refractory courses of infection. In this review, the various clinical infections where SCVs can be expected and isolated, diagnostic procedures for optimized species confirmation, and the pathogenesis of SCVs, including defined underlying molecular mechanisms and the phenotype switch phenomenon, are presented. Moreover, relevant animal models and suggested treatment regimens, as well as the requirements for future research areas, are highlighted.

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Section: Influence Of Scv Phenotype On Antibiotic Susceptibilitiesmentioning

confidence: 99%

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

2016

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“…The cefoxitin MICs of the tested mutants were comparable to those from corresponding NPs and CMs. Interestingly, intracellular forms of menD mutant SCVs were shown to be hypersusceptible to BLAs in a recent study (18).…”

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confidence: 95%

In Vitro Susceptibility of Clinical Staphylococcus aureus Small-Colony Variants to β-Lactam and Non-β-Lactam Antibiotics

Idelevich

Kriegeskorte

Schleimer

et al. 2018

Antimicrob Agents Chemother

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The small-colony variant (SCV) phenotype has been associated with relapsing and antibiotic-refractory infections. However, little is known about the activities of antibiotics on clinical SCVs. Here, we demonstrated that SCVs without detectable auxotrophies were at least as susceptible to most β-lactam and non-β-lactam antibiotics as their corresponding clonally identical strains with a normal phenotype. After prolonged incubation, a regrowth phenomenon has been observed in gradient diffusion inhibition zones irrespective of the strains' phenotype.

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“…25, 29, 30 Three well defined SCV auxotrophisms have been identified in which wild-type growth can be restored by supplementation with thymidine, 31 CO 2 , 27, 32 and molecules that complement deficiencies in electron-transport. 33–35 Typically, for electron-transport deficient SCVs, the wild-type phenotype can be restored by supplementation with menaquinone (MK, Vitamin K2) or menadione (MD, Vitamin K3). 34, 36 In some cases, this auxotrophism has been directly linked to mutations in enzymes that constitute the MK biosynthesis pathway.…”

Section: Introductionmentioning

confidence: 99%

A Methyl 4-Oxo-4-phenylbut-2-enoate with in Vivo Activity against MRSA That Inhibits MenB in the Bacterial Menaquinone Biosynthesis Pathway

Matarlo

Daryaee

et al. 2016

ACS Infect. Dis.

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4-Oxo-4-phenyl-but-2-enoates inhibit MenB, the 1,4-dihydroxyl-2-naphthoyl-CoA synthase in the bacterial menaquinone (MK) biosynthesis pathway, through the formation of an adduct with coenzyme A (CoA). Here, we show that the corresponding methyl butenoates have MIC values as low as 0.35–0.75 µg/mL against drug sensitive and resistant strains of Staphylococcus aureus. Mode of action studies on the most potent compound, methyl 4-(4-chlorophenyl)-4-oxobut-2-enoate (1), reveal that 1 is converted into the corresponding CoA adduct in S. aureus cells, and that this adduct binds to the S. aureus MenB (saMenB) with a Kd value of 2 µM. The antibacterial spectrum of 1 is limited to bacteria that utilize MK for respiration, and the activity of 1 can be complemented with exogenous MK or menadione. Finally, treatment of methicillin-resistant S. aureus (MRSA) with 1 results in the small colony variant phenotype and thus 1 phenocopies knockout of the menB gene. Taken together the data indicate that the antibacterial activity of 1 results from a specific effect on MK biosynthesis. We also evaluated the in vivo efficacy of 1 using two mouse models of MRSA infection. Notably, compound 1 increased survival in a systemic infection model and resulted in a dose-dependent decrease in bacterial load in a thigh infection model, validating MenB as a target for the development of new anti-MRSA candidates.

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Intracellular forms of menadione-dependent small-colony variants of methicillin-resistant Staphylococcus aureus are hypersusceptible to -lactams in a THP-1 cell model due to cooperation between vacuolar acidic pH and oxidant species

Abstract: Cooperation between acidic pH and oxidant species confers high potency to β-lactams against intracellular forms of menD SCVs of MRSA.

Cited by 15 publications

References 23 publications

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

In Vitro Susceptibility of Clinical Staphylococcus aureus Small-Colony Variants to β-Lactam and Non-β-Lactam Antibiotics

A Methyl 4-Oxo-4-phenylbut-2-enoate with in Vivo Activity against MRSA That Inhibits MenB in the Bacterial Menaquinone Biosynthesis Pathway

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