Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA

El-Halfawy, Omar M.; Czarny, Tomasz L.; Flannagan, Ronald S.; Day, Jonathan; Bozelli, José Carlos; Kuiack, Robert C.; Salim, Ahmed; Eckert, Philip; Epand, Richard M.; McGavin, Martin J.; Organ, Michael G.; Heinrichs, David E.; Brown, Eric D.

doi:10.1038/s41589-019-0401-8

Cited by 70 publications

(52 citation statements)

References 51 publications

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“…To fill this gap in a way that considerably lower the resistance potential, new non-conventional ways had to be explored. Investigated alternatives include plant-derived compounds [4], bacteriophages and phage lysins [5], RNA-based therapeutics [6], antimicrobial adjuvants [7], and antimicrobial peptides (AMP) [8].…”

Section: Introductionmentioning

confidence: 99%

A Rapid Lysostaphin Production Approach and a Convenient Novel Lysostaphin Loaded Nano-emulgel; As a Sustainable Low-Cost Methicillin-Resistant Staphylococcus aureus Combating Platform

et al. 2020

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Staphylococcus aureus is a Gram-positive pathogen that is capable of infecting almost every organ in the human body. Alarmingly, the rapid emergence of methicillin-resistant S. aureus strains (MRSA) jeopardizes the available treatment options. Herein, we propose sustainable, low-cost production of recombinant lysostaphin (rLST), which is a native bacteriocin destroying the staphylococcal cell wall through its endopeptidase activity. We combined the use of E. coli BL21(DE3)/pET15b, factorial design, and simple Ni-NTA affinity chromatography to optimize rLST production. The enzyme yield was up to 50 mg/L culture, surpassing reported systems. Our rLST demonstrated superlative biofilm combating ability by inhibiting staphylococcal biofilms formation and detachment of already formed biofilms, compared to vancomycin and linezolid. Furthermore, we aimed at developing a novel rLST topical formula targeting staphylococcal skin infections. The phase inversion composition (PIC) method fulfilled this aim with its simple preparatory steps and affordable components. LST nano-emulgel (LNEG) was able to extend active LST release up to 8 h and cure skin infections in a murine skin model. We are introducing a rapid, convenient rLST production platform with an outcome of pure, active rLST incorporated into an effective LNEG formula with scaling-up potential to satisfy the needs of both research and therapeutic purposes.

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Section: Introductionmentioning

confidence: 99%

A Rapid Lysostaphin Production Approach and a Convenient Novel Lysostaphin Loaded Nano-emulgel; As a Sustainable Low-Cost Methicillin-Resistant Staphylococcus aureus Combating Platform

et al. 2020

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“…[3][4][5] The most serious infections such as endocarditis, osteomyelitis, necrotizing pneumonia and sepsis occur on dissemination of the bacteria into the bloodstream. 6 In S. aureus, SarA is a 14.7 kDa winged helix turn helix transcriptional activator and known to up-regulate the agr based quorum sensing system to elicit the exoprotein level. 7,8 Simultaneously, the SarA indirect role on down-regulation of various other regulatory loci such as rot, sarS, sarV, sarT are also well documented.…”

Section: Introductionmentioning

confidence: 99%

Retracted Article: Functional disruption of staphylococcal accessory regulator A from Staphylococcus aureus by silver ions

et al. 2020

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“…Nevertheless, although S. aureus is concurrently exposed to multiple environmental signals and mediators of innate immunity at sites of colonization, its ability to sense and respond to these signals is typically studied in a singular manner (20)(21)(22). In this context, our recent work has alluded to the possibility that S. aureus could effectively multitask in response to sensing disparate environmental signals through the GraS sensor kinase (7,23).…”

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confidence: 99%

Novel Functions and Signaling Specificity for the GraS Sensor Kinase of Staphylococcus aureus in Response to Acidic pH

2020

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Although the GraS sensor kinase of Staphylococcus aureus is known for sensing of and resistance to cationic antimicrobial peptides (CAMPs), we recently established that it also signals in response to acidic pH which is encountered on human skin concurrently with CAMPs, antimicrobial unsaturated free fatty acids (uFFA), and calcium. We therefore evaluated how these environmental signals would affect GraS function and resistance to antimicrobial uFFA. Growth at pH 5.5 promoted increased resistance of S. aureus USA300 to linoleic- and arachidonic acid, but not palmitoleic or sapienic acid. However, enhanced resistance to these C16:1 uFFA was achieved by supplementing acidic medium with 0.5 mM calcium or subinhibitory CAMPs. Enhanced resistance to uFFA at acidic pH was dependent on GraS and GraS-dependent expression of the lysyl-phosphatidylglycerol synthase enzyme MprF, through a mechanism that did not require the lysyl-transferase function of MprF. In addition to enhanced resistance to antimicrobial uFFA, acidic pH also promoted increased production of secreted proteases in a GraS-dependent manner. During growth at pH 5.5, downstream phenotypes of signaling through GraS, including resistance to uFFA, MprF-dependent addition of positive charge to the cell surface, and increased production of secreted proteases all occurred independently of acidic amino acids in the extra-cytoplasmic sensor loop of GraS that were previously found to be required for sensing of CAMPs. Cumulatively, our data indicate that signaling through GraS at acidic pH occurs through a mechanism that is distinct from that described for CAMPs, leading to increased resistance to antimicrobial uFFA and production of secreted proteases. IMPORTANCE: Staphylococcus aureus asymptomatically colonizes 30% humans but is also a leading cause of infectious morbidity and mortality. Since infections are typically initiated by the same strain associated with asymptomatic colonization of the nose or skin, it is important to understand how the microbe can endure exposure to harsh conditions that successfully restrict the growth of other bacteria, including a combination of acidic pH, antimicrobial peptides and antimicrobial fatty acids. The significance of our research is in showing that acidic pH combined with antimicrobial peptide or environmental calcium can signal through a single membrane sensor protein to promote traits that may aid in survival, including modification of cell surface properties, increased resistance to antimicrobial fatty acids, and enhanced production of secreted proteases.

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Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA

Cited by 70 publications

References 51 publications

A Rapid Lysostaphin Production Approach and a Convenient Novel Lysostaphin Loaded Nano-emulgel; As a Sustainable Low-Cost Methicillin-Resistant Staphylococcus aureus Combating Platform

A Rapid Lysostaphin Production Approach and a Convenient Novel Lysostaphin Loaded Nano-emulgel; As a Sustainable Low-Cost Methicillin-Resistant Staphylococcus aureus Combating Platform

Retracted Article: Functional disruption of staphylococcal accessory regulator A from Staphylococcus aureus by silver ions

Novel Functions and Signaling Specificity for the GraS Sensor Kinase of Staphylococcus aureus in Response to Acidic pH

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