Activation of BlaR1 Protein of Methicillin-resistant Staphylococcus aureus, Its Proteolytic Processing, and Recovery from Induction of Resistance

Llarrull, Leticia I.; Tóth, Márta; Champion, Matthew M.; Mobashery, Shahriar

doi:10.1074/jbc.m111.288985

Cited by 57 publications

(111 citation statements)

References 31 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…Again, the process in the case of mecA is not well characterized but is inferred from research on the bla system. Here, BlaR1 undergoes specific proteolysis at two sites, the cytoplasmic MPD and a second extracellular site, resulting in the shedding of the sensor domain (97). Cleavage in the proteolytic domain is thought to be autolytic, with type I signal peptidase responsible for the shedding of the sensor domain (97).…”

Section: Regulation Of Methicillin Resistancementioning

confidence: 99%

Mechanisms of Methicillin Resistance in Staphylococcus aureus

Peacock

Paterson

2015

Annu. Rev. Biochem.

489

371

View full text Add to dashboard Cite

Staphylococcus aureus is a major human and veterinary pathogen worldwide. Methicillin-resistant S. aureus (MRSA) poses a significant and enduring problem to the treatment of infection by such strains. Resistance is usually conferred by the acquisition of a nonnative gene encoding a penicillin-binding protein (PBP2a), with significantly lower affinity for β-lactams. This resistance allows cell-wall biosynthesis, the target of β-lactams, to continue even in the presence of typically inhibitory concentrations of antibiotic. PBP2a is encoded by the mecA gene, which is carried on a distinct mobile genetic element (SCCmec), the expression of which is controlled through a proteolytic signal transduction pathway comprising a sensor protein (MecR1) and a repressor (MecI). Many of the molecular and biochemical mechanisms underlying methicillin resistance in S. aureus have been elucidated, including regulatory events and the structure of key proteins. Here we review recent advances in this area.

show abstract

Section: Regulation Of Methicillin Resistancementioning

confidence: 99%

Mechanisms of Methicillin Resistance in Staphylococcus aureus

Peacock

Paterson

2015

Annu. Rev. Biochem.

489

371

View full text Add to dashboard Cite

show abstract

“…Table 3 shows the K i and IC 50 of the penem compounds with the enzymes OXA-1 and OXA-24. The data suggest that penem 1 and penem 3 are good inhibitors against both OXA-1 and OXA-24 because their K i and IC 50 values are very low (at nM level).…”

Section: Kinetic Data For Penems 1 and 3 Reacting With Oxa-1 And Oxa-24mentioning

confidence: 99%

“…IC 50 , defined as the inhibitor concentration resulting in a reduction of NCF (100 M) hydrolysis by 50%, was determined by measurements of initial velocities after 5-min preincubation of enzyme with inhibitor.…”

mentioning

confidence: 99%

The Different Inhibition Mechanisms of OXA-1 and OXA-24 β-Lactamases Are Determined by the Stability of Active Site Carboxylated Lysine

Che

Bethel

Pusztai-Carey

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: OXA-1 and OXA-24 are class D ␤-lactamases that resist clinically used inhibitors. Results: Spectroscopic methods and kinetic measurements show that penem drug candidates are good inhibitors of OXA-1 but are rapidly hydrolyzed by OXA-24. Conclusion: An active site water in OXA-24 aids the reversible carboxylation of Lys-84, enabling many reaction cycles. Significance: Understanding the mechanism of class D ␤-lactamases is vital for drug development.

show abstract

“…The highly tuned specificity of Of1 for β-lactam antibiotics in MRSA largely rules out the general potentiation mechanisms, such as efflux pump inhibition and enhancement of membrane permeability (37). Instead, Of1 may selectively target β-lactam-specific resistance mechanism, such as β-lactam-induced expression of the mecA and/or blaZ genes, which encode PBP2a and β-lactamase, respectively (3,(38)(39)(40)(41). Because Of1 can potentiate the combination of amoxicillin and the β-lactamase inhibitor clavulanic acid, and Of1 does not have the reactive β-lactam functional group, it is highly likely that Of1 modifies the resistance of MRSA via an unknown mechanism.…”

Section: Screening Of Polycyclic Indolines That Potentiate the Activimentioning

confidence: 99%

Bio-inspired synthesis yields a tricyclic indoline that selectively resensitizes methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics

Podoll

Liu

Chang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

112

View full text Add to dashboard Cite

The continuous emergence of resistant bacteria has become a major worldwide health threat. The current development of new antibacterials has lagged far behind. To discover reagents to fight against resistant bacteria, we initiated a chemical approach by synthesizing and screening a small molecule library, reminiscent of the polycyclic indole alkaloids. Indole alkaloids are a class of structurally diverse natural products, many of which were isolated from plants that have been used as traditional medicine for millennia. Specifically, we adapted an evolutionarily conserved biosynthetic strategy and developed a concise and unified diversity synthesis pathway. Using this pathway, we synthesized 120 polycyclic indolines that contain 26 distinct skeletons and a wide variety of functional groups. A tricyclic indoline, Of1, was discovered to selectively potentiate the activity of β-lactam antibiotics in multidrug-resistant methicillin-resistant Staphylococcus aureus (MRSA), but not in methicillin-sensitive S. aureus. In addition, we found that Of1 itself does not have antiproliferative activity but can resensitize several MRSA strains to the β-lactam antibiotics that are widely used in the clinic, such as an extended-spectrum β-lactam antibiotic amoxicillin/clavulanic acid and a first-generation cephalosporin cefazolin. These data suggest that Of1 is a unique selective resistancemodifying agent for β-lactam antibiotics, and it may be further developed to fight against resistant bacteria in the clinic.

show abstract

Activation of BlaR1 Protein of Methicillin-resistant Staphylococcus aureus, Its Proteolytic Processing, and Recovery from Induction of Resistance

Cited by 57 publications

References 31 publications

Mechanisms of Methicillin Resistance in Staphylococcus aureus

Mechanisms of Methicillin Resistance in Staphylococcus aureus

The Different Inhibition Mechanisms of OXA-1 and OXA-24 β-Lactamases Are Determined by the Stability of Active Site Carboxylated Lysine

Bio-inspired synthesis yields a tricyclic indoline that selectively resensitizes methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics

Contact Info

Product

Resources

About