Penicillin binding protein 2a: An overview and a medicinal chemistry perspective

Shalaby, Menna-Allah W.; Dokla, Eman M.E.; Serya, Rabah A. T.; Abouzid, Khaled A. M.

doi:10.1016/j.ejmech.2020.112312

Cited by 90 publications

(46 citation statements)

References 117 publications

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“…On the other hand, molecular docking showed a possible interaction between terpinen-4-ol and penicillin-binding protein 2a (PBP2a), which is one of the main molecules involved in S. aureus resistance to beta-lactam drugs due to its low affinity for them and to its transpeptidase activity that allows cell wall biosynthesis [ 19 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

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Terpinen-4-ol as an Antibacterial and Antibiofilm Agent against Staphylococcus aureus

Cordeiro

Figueiredo

Souza

et al. 2020

IJMS

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Staphylococcus aureus is able to rapidly develop mechanisms of resistance to various drugs and to form strong biofilms, which makes it necessary to develop new antibacterial drugs. The essential oil of Melaleuca alternifolia is used as an antibacterial, a property believed to be mainly due to the presence of terpinen-4-ol. Based on this, the objective of this study was to evaluate the antibacterial and antibiofilm potential of terpinen-4-ol against S. aureus. The Minimal Inhibitory and Minimal Bactericidal Concentrations (MIC and MBC) of terpinen-4-ol were determined, and the effect of its combination with antibacterial drugs as well as its activity against S. aureus biofilms were evaluated. In addition, an in silico analysis of its pharmacokinetic parameters and a molecular docking analysis were performed. Terpinen-4-ol presented a MIC of 0.25% (v/v) and an MBC of 0.5% (v/v) (bactericidal action); its association with antibacterials was also effective. Terpinen-4-ol has good antibiofilm activity, and the in silico results indicated adequate absorption and distribution of the molecule in vivo. Molecular docking indicated that penicillin-binding protein 2a is a possible target of terpinen-4-ol in S. aureus. This work highlights the good potential of terpinen-4-ol as an antibacterial product and provides support for future pharmacological studies of this molecule, aiming at its therapeutic application.

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Section: Resultsmentioning

confidence: 99%

“…The production of PBP2a is the main mechanism developed by MRSA inducing broad clinical resistance to beta-lactams. MRSA resistance is mediated through the acquisition of a gene cassette containing the gene mec A, which encodes the low-affinity altered transpeptidase PBP2a [ 19 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

Terpinen-4-ol as an Antibacterial and Antibiofilm Agent against Staphylococcus aureus

Cordeiro

Figueiredo

Souza

et al. 2020

IJMS

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“…Such a contradiction could be attributed to the presence of TYR-446 at the gate of the PBP2a active site ( Figure 3 ), which hinders its accessibility by such large and highly polar molecules. Only small and relatively nonpolar compounds can access such hydrophobic narrow active site grooves (e.g., ceftobiprole (25), Figure 3 A) [ 4 , 13 ]. MDS of a system-contained diosmin (11) near to the PBP2a active site (25 Å away from SER-403) supported this suggestion, where the polar carbohydrate moiety clashed with the hydrophobic gate-keeper residues (e.g., TYR-446) hindering its accessibility inside the active site groove.…”

Section: Resultsmentioning

confidence: 99%

Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study

et al. 2020

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Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant Staphylococcus aureus (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class of compounds against MRSA, particularly the non-glycosylated ones. On the other hand, the glycosylated derivatives, along with the flavonolignan silibinin A, were able to restore the inhibitory activity of ampicillin against MRSA. To explore the mode of action of this class, they were subjected to an extensive inverse virtual screening (IVS), which suggested penicillin-binding protein 2a (PBP2a) as a possible target that mediates both the antibacterial and the antibiotic-synergistic effects of this class of compounds. Further molecular docking and molecular dynamic simulation experiments were conducted to support the primary IVS and the in vitro results and to study their binding modes with PBP2a. Our findings shed a light on plant-derived natural products, notably flavonoids, as a promising and readily available source for future adjuvant antimicrobial therapy against resistant strains.

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“…A critical nding in this study is that B. subtilis CFS increased the susceptibility of S. aureus to penicillin in vitro and in vivo. Generally, S. aureus strains are found to be resistant to almost all β-lactam antibodies as they produce β-lactamase that breaks down β-lactam ring or a penicillin-binding protein called PBP2a that has a low binding a nity to β-lactam antibodies [14,30]. Our data show that B. subtilis CFS suppresses the expression of proteins with molecular weights ranging from 55 to 100 kDa.…”

Section: Discussionmentioning

confidence: 78%

Bacillus Subtilis Revives Conventional Antibiotics Against Staphylococcus Aureus Osteomyelitis

Zhang

Wang

Liu

et al. 2021

Preprint

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As treatment of Staphylococcus aureus osteomyelitis is often hindered by the development of antibiotic tolerance, novel antibacterial therapeutics are required. Here we found that the cell-free supernatant of Bacillus subtilis (B. subtilis CFS) killed planktonic and biofilm S. aureus, and increased S. aureus susceptibility to penicillin and gentamicin as well. Further study showed that B. subtilis CFS suppressed the expression of the genes involved in adhesive molecules (Cna and ClfA), virulence factor Hla, quorum sensing (argA, argB and RNAIII) and biofilm formation (Ica and sarA) in S. aureus. Additionally, our data showed that B. subtilis CFS changed the membrane components and increased membrane permeabilization of S. aureus. Finally, we demonstrated that B. subtilis CFS increased considerably the susceptibility of S. aureus to penicillin and effectively reduced S. aureus burdens in a mouse model of implant-associated osteomyelitis. These findings support that B. subtilis CFS may be a potential resistance-modifying agent against S. aureus osteomyelitis.

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Penicillin binding protein 2a: An overview and a medicinal chemistry perspective

Cited by 90 publications

References 117 publications

Terpinen-4-ol as an Antibacterial and Antibiofilm Agent against Staphylococcus aureus

Terpinen-4-ol as an Antibacterial and Antibiofilm Agent against Staphylococcus aureus

Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study

Bacillus Subtilis Revives Conventional Antibiotics Against Staphylococcus Aureus Osteomyelitis

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