Sub-inhibitory membrane damage undermines Staphylococcus aureus virulence

Hershkovits, Ayelet S; Pozdnyakov, Igor R.; Meir, Ohad; Mor, Amram

doi:10.1016/j.bbamem.2019.04.002

Cited by 6 publications

(9 citation statements)

References 62 publications

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Section: Mechanistic Studiesmentioning

confidence: 99%

“…Alternatively, plasma resistance may be linked to bacterial virulence factors (e.g., pseudomonal alkaline protease which cleaves C2 complements, thereby blocking both classical and lectin pathways) [65]. In this case too, C14(ω5)OOc10O might overcome the problem, as suggested by investigations of analogous borderline hydrophobic OACs linking partial depolarization of staphylococci to inhibition of virulence and resistance factors [18,19]. The wild-type E. coli strain AG100 and its isogenic ΔacrAB mutant AG100A were used to determine the MIC of OACs and of two known acrAB-TolC substrates: the AMP LL-37 and the macrolide antibiotic erythromycin that are normally inefficient against GNB.…”

Section: Mechanistic Studiesmentioning

confidence: 99%

“…Indeed, unlike outright hydrophobic AMPs that tend to disrupt both membranes of GNB abruptly [9][10][11], borderline hydrophobic analogs were proposed to maintain the OM permeabilization capacity but may additionally instigate little more than transient superficial damages to the inner membrane (IM) [12][13][14][15]. While not fully understood, the latter activity was linked to a variety of processes (such as restricted efflux [16], inhibited expression of antibiotic resistance factors [17][18][19] and pathogens sensitization to diverse antimicrobials [20][21][22][23][24]) some of which, may open a window of opportunity for therapeutic exploitation. Thus, potentiated agents would encompass exogenous antibiotics as well as endogenous bactericidal capabilities of innate plasma complements [25].…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy

2021

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We describe the design and attributes of a linear pentapeptide-like derivative (C14(ω5)OOc10O) screened for its ability to elicit bactericidal competences of plasma constituents against Gram-negative bacteria (GNB). In simpler culture media, the lipopeptide revealed high aptitudes to sensitize resilient GNB to hydrophobic and/or efflux-substrate antibiotics, whereas in their absence, C14(ω5)OOc10O only briefly delayed bacterial proliferation. Instead, at low micromolar concentrations, the lipopeptide has rapidly lowered bacterial proton and ATP levels, although significantly less than upon treatment with its bactericidal analog. Mechanistic studies support a two-step scenario providing a plausible explanation for the lipopeptide’s biological outcomes against GNB: initially, C14(ω5)OOc10O permeabilizes the outer membrane similarly to polymyxin B, albeit in a manner not necessitating as much LPS-binding affinity. Subsequently, C14(ω5)OOc10O would interact with the inner membrane gently yet intensively enough to restrain membrane-protein functions such as drug efflux and/or ATP generation, while averting the harsher inner membrane perturbations that mediate the fatal outcome associated with bactericidal peers. Preliminary in vivo studies where skin wound infections were introduced in mice, revealed a significant efficacy in affecting bacterial viability upon topical treatment with creams containing C14(ω5)OOc10O, whereas synergistic combination therapies were able to secure the pathogen’s eradication. Further, capitalizing on the finding that C14(ω5)OOc10O plasma-potentiating concentrations were attainable in mice blood at sub-maximal tolerated doses, we used a urinary tract infection model to acquire evidence for the lipopeptide’s systemic capacity to reduce the kidney’s bacterial loads. Collectively, the data establish the role of C14(ω5)OOc10O as a compelling antibacterial potentiator and suggest its drug-like potential.

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Section: Mechanistic Studiesmentioning

confidence: 99%

Section: Mechanistic Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy

2021

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“…These are properties known to be impacted by antibiotics and thus lead to decreased agr expression ( Attia et al, 2010 ; Dengler et al, 2011 ). In fact, a recent study reports that the membrane-active lipopeptide, C 10 OOc 12 O, at sub-growth inhibitory concentrations to MRSA causes mild membrane depolarization with an accompanying reduction of lipase and α-toxin outputs and resensitization to oxacillin ( Hershkovits et al, 2019 ). Another study on oxacillin showed that sub-growth inhibitory concentrations of the β-lactam antibiotic caused an altered cell membrane architecture in MRSA while also downregulating agr , resulting in reduced virulence in vitro and in vivo and enhanced killing in vivo ( Waters et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Castaneroxy A From the Leaves of Castanea sativa Inhibits Virulence in Staphylococcus aureus

et al. 2021

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Methicillin-resistant Staphylococcus aureus (MRSA) represents one of the most serious infectious disease concerns worldwide, with the CDC labeling it a “serious threat” in 2019. The current arsenal of antibiotics works by targeting bacterial growth and survival, which exerts great selective pressure for the development of resistance. The development of novel anti-infectives that inhibit quorum sensing and thus virulence in MRSA has been recurrently proposed as a promising therapeutic approach. In a follow-up of a study examining the MRSA quorum sensing inhibitory activity of extracts of Italian plants used in local traditional medicine, 224C-F2 was reported as a bioactive fraction of a Castanea sativa (European chestnut) leaf extract. The fraction demonstrated high activity in vitro and effective attenuation of MRSA pathogenicity in a mouse model of skin infection. Through further bioassay-guided fractionation using reverse-phase high performance liquid chromatography, a novel hydroperoxy cycloartane triterpenoid, castaneroxy A (1), was isolated. Its structure was established by nuclear magnetic resonance, mass spectrometry and X-ray diffraction analyses. Isomers of 1 were also detected in an adjacent fraction. In a series of assays assessing inhibition of markers of MRSA virulence, 1 exerted activities in the low micromolar range. It inhibited agr::P3 activation (IC50 = 31.72 µM), δ-toxin production (IC50 = 31.72 µM in NRS385), supernatant cytotoxicity to HaCaT human keratinocytes (IC50 = 7.93 µM in NRS385), and rabbit erythrocyte hemolytic activity (IC50 = 7.93 µM in LAC). Compound 1 did not inhibit biofilm production, and at high concentrations it exerted cytotoxicity against human keratinocytes greater than that of 224C-F2. Finally, 1 reduced dermonecrosis in a murine model of MRSA infection. The results establish 1 as a promising antivirulence candidate for development against MRSA.

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“…Treatment with 1.5 μM of the membrane-active lipopeptide compound C 10 OOC 12 O, MRSA USA300 cells exhibit sustained mild membrane damages, and Hershkovits et al . speculated that such damaged bacterial membrane may not yet damaged enough at sub-MIC concentration of lipopeptide to the leakage of larger chemical molecules, such as ATP, which indeed happens at the MIC concentration of C 10 OOC 12 O (12.5 μM in Luria Bertani medium) [26] .…”

Section: Effects Of the Sub-mics Of Antibiotics On The Morphology Of S Aureusmentioning

confidence: 99%

Virulence alterations in staphylococcus aureus upon treatment with the sub-inhibitory concentrations of antibiotics

Chen

Zhou

Huang

et al. 2021

Journal of Advanced Research

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Sub-inhibitory membrane damage undermines Staphylococcus aureus virulence

Cited by 6 publications

References 62 publications

Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy

Mechanistic Studies of Antibiotic Adjuvants Reducing Kidney’s Bacterial Loads upon Systemic Monotherapy

Castaneroxy A From the Leaves of Castanea sativa Inhibits Virulence in Staphylococcus aureus

Virulence alterations in staphylococcus aureus upon treatment with the sub-inhibitory concentrations of antibiotics

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