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Discovery of adjuvants with antibacterial potentiation activity against carbapenemase-producing Enterobacterales based on in silico virtual screening.
- Source :
-
International Journal of Antimicrobial Agents . Feb2024, Vol. 63 Issue 2, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- • Libraries of small molecules containing more than 30,000 small molecules were docked to carbapenemases (KPC-2, NDM-5) through in silico virtual screening. • Ibandronate, azacytidine, ribostamycin sulphate and cidofovir exhibited synergistic or additive antibacterial activity in combination with meropenem in vitro. • The combination of meropenem and azacytidine showed high efficacy in a mouse sepsis model infected with an NDM-5-producing clinical strain, with a 100% survival rate, decreased bacterial burden and alleviated pathological deterioration. • All 4 promising candidates were associated with low toxicity and good biocompatibility. Bacterial multi-drug resistance has become a concern worldwide, especially after the emergence of carbapenemases. Adjuvants with antibacterial potentiation activity can resensitise drug-resistant strains to carbapenems. However, only a few adjuvants with antibacterial potentiation activity are currently available in clinical practice. Here, we first docked the library containing more than 30,000 small molecules to carbapenemases including Klebsiella pneumoniae carbapenemase 2 (KPC-2) and New Delhi metallo- β -lactamase-5 (NDM-5), through in silico virtual screening to obtain lead compounds against carbapenemase-producing Enterobacterales. Meanwhile, the in vitro antibacterial potentiation assays revealed that ibandronate, azacytidine, ribostamycin sulfate and cidofovir exhibited synergistic or additive activity in the presence of meropenem, with good biocompatibility based on red blood cell hemolysis and cell viability tests. Furthermore, the combination of meropenem and azacytidine showed high efficacy in a mouse sepsis model infected with an NDM-5-producing clinical strain, with a 100% survival rate, decreased bacterial burden and alleviated pathological deterioration. These results suggest that the virtual screening is a promising strategy to identify new antibiotic adjuvants targeting carbapenemase-producing Enterobacterales. [Display omitted] [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09248579
- Volume :
- 63
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- International Journal of Antimicrobial Agents
- Publication Type :
- Academic Journal
- Accession number :
- 175411572
- Full Text :
- https://doi.org/10.1016/j.ijantimicag.2023.107076