Autor: |
Sarmistha Biswal, Karina Caetano, Diamond Jain, Anusha Sarrila, Tulika Munshi, Rachael Dickman, Alethea B. Tabor, Surya Narayan Rath, Sanjib Bhakta, Anindya S. Ghosh |
Jazyk: |
angličtina |
Rok vydání: |
2023 |
Předmět: |
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Zdroj: |
Antibiotics, Vol 12, Iss 3, p 553 (2023) |
Druh dokumentu: |
article |
ISSN: |
2079-6382 |
DOI: |
10.3390/antibiotics12030553 |
Popis: |
Class A serine β-lactamases (SBLs) have a conserved non-active site structural domain called the omega loop (Ω-loop), in which a glutamic acid residue is believed to be directly involved in the hydrolysis of β-lactam antibiotics by providing a water molecule during catalysis. We aimed to design and characterise potential pentapeptides to mask the function of the Ω-loop of β-lactamases and reduce their efficacy, along with potentiating the β-lactam antibiotics and eventually decreasing β-lactam resistance. Considering the Ω-loop sequence as a template, a group of pentapeptide models were designed, validated through docking, and synthesised using solid-phase peptide synthesis (SPPS). To check whether the β-lactamases (BLAs) were inhibited, we expressed specific BLAs (TEM-1 and SHV-14) and evaluated the trans-expression through a broth dilution method and an agar dilution method (HT-SPOTi). To further support our claim, we conducted a kinetic analysis of BLAs with the peptides and employed molecular dynamics (MD) simulations of peptides. The individual presence of six histidine-based peptides (TSHLH, ETHIH, ESRLH, ESHIH, ESRIH, and TYHLH) reduced β-lactam resistance in the strains harbouring BLAs. Subsequently, we found that the combinational effect of these peptides and β-lactams sensitised the bacteria towards the β-lactam drugs. We hypothesize that the antimicrobial peptides obtained might be considered among the novel inhibitors that can be used specifically against the Ω-loop of the β-lactamases. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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