PBP4: A New Perspective on Staphylococcus aureus β-Lactam Resistance

Costa, Thaina Miranda da; Oliveira, Carolina Roberte de; Chambers, Henry F.; Chatterjee, Som S.

doi:10.3390/microorganisms6030057

Cited by 40 publications

(32 citation statements)

References 44 publications

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“…Interestingly, inhibition of PBP4 activity has been shown to diminish cell wall cross-linking in β-lactam heteroresistant MRSA strains but had no effect on cross-linking in homoresistant strains (48). Currently, little is known about the regulation of PBP4 expression (49); however, further investigations into the effect of NaHCO 3 on PBP4 protein production may offer additional insights into mechanisms underlying NaHCO 3 -responsive versus NaHCO 3 -nonresponsive phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Ersoy

Abdelhady

et al. 2019

Antimicrob Agents Chemother

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Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as “resistant” to β-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the antistaphylococcal β-lactams oxacillin and cefazolin (NaHCO3 responsive) and one resistant to such agents (NaHCO3 nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.

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Section: Discussionmentioning

confidence: 99%

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Ersoy

Abdelhady

et al. 2019

Antimicrob Agents Chemother

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“…It can be assumed that pbp4 expression is tightly controlled, as it is dynamically tuned in response to local antibiotic concentrations [49]. Recently, studies have shown that PBP4 may play an important role in S. aureus resistance to β-lactam antibiotics [40,[50][51][52][53]. Therefore, other factors contributing to the regulation of pbp4 activity should be investigated further, including wall teichoic acids, shown to act as spatial and temporal regulations of PBP4 mediated peptidoglycan crosslinking [54], and PBP2, which has been shown to interact with PBP4 during cell wall synthesis [55].…”

Section: Plos Pathogensmentioning

confidence: 99%

Identification of Penicillin Binding Protein 4 (PBP4) as a critical factor for Staphylococcus aureus bone invasion during osteomyelitis in mice

et al. 2020

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Staphylococcus aureus infection of bone is challenging to treat because it colonizes the osteocyte lacuno-canalicular network (OLCN) of cortical bone. To elucidate factors involved in OLCN invasion and identify novel drug targets, we completed a hypothesis-driven screen of 24 S. aureus transposon insertion mutant strains for their ability to propagate through 0.5 μm-sized pores in the Microfluidic Silicon Membrane Canalicular Arrays (μSiM-CA), developed to model S. aureus invasion of the OLCN. This screen identified the uncanonical S. aureus transpeptidase, penicillin binding protein 4 (PBP4), as a necessary gene for S. aureus deformation and propagation through nanopores. In vivo studies revealed that Δpbp4 infected tibiae treated with vancomycin showed a significant 12-fold reduction in bacterial load compared to WT infected tibiae treated with vancomycin (p<0.05). Additionally, Δpbp4 infected tibiae displayed a remarkable decrease in pathogenic bone-loss at the implant site with and without vancomycin therapy. Most importantly, Δpbp4 S. aureus failed to invade and colonize the OLCN despite high bacterial loads on the implant and in adjacent tissues. Together, these results demonstrate that PBP4 is required for S. aureus colonization of the OLCN and suggest that inhibitors may be synergistic with standard of care antibiotics ineffective against bacteria within the OLCN.

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“…Interestingly, inhibition of PBP4 activity has been shown to diminish cell wall cross-linking in β-lactam hetero-resistant MRSA strains, but had no effect on cross-linking in homo-resistant strains (48). Currently, little is known about the regulation of PBP4 expression (49); however, further investigations into the effect of NaHCO 3 on PBP4 protein production may offer additional insights into mechanisms underlying NaHCO 3 -responsive vs NaHCO 3 -nonresponsive phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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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PBP4: A New Perspective on Staphylococcus aureus β-Lactam Resistance

Cited by 40 publications

References 44 publications

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Identification of Penicillin Binding Protein 4 (PBP4) as a critical factor for Staphylococcus aureus bone invasion during osteomyelitis in mice

Bicarbonate Resensitization of Methicillin-ResistantStaphylococcus aureusto β-Lactam Antibiotics

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