| Full text | |
| Author(s): |
Fanti, Rebeka C.
;
Vasconcelos, Stanley N. S.
;
Catta-Preta, Carolina M. C.
;
Sullivan, Jaryd R. .
;
Riboldi, Gustavo P.
;
Reis, Caio V. dos
;
Ramos, Priscila Z.
;
Edwards, Aled M.
;
Behr, Marcel A. .
;
Counago, Rafael M.
Total Authors: 10
|
| Document type: | Journal article |
| Source: | ACS INFECTIOUS DISEASES; v. 8, n. 8, p. 19-pg., 2022-07-11. |
| Abstract | |
New antibiotics are urgently needed to counter the emergence of antimicrobial-resistant pathogenic bacteria. A major challenge in antibiotic drug discovery is to turn potent biochemical inhibitors of essential bacterial components into effective antimicrobials. This difficulty is underpinned by a lack of methods to investigate the physicochemical properties needed for candidate antibiotics to permeate the bacterial cell envelope and avoid clearance by the action of bacterial efflux pumps. To address these issues, here we used a target engagement assay to measure the equilibrium and kinetic binding parameters of antibiotics targeting dihydrofolate reductase (DHFR) in live bacteria. We also used this assay to identify novel DHFR ligands having antimicrobial activity . We validated this approach using the Gram-negative bacteria Escherichia coli and the emerging human pathogen Mycobacterium abscessus. We expect the use of target engagement assays in bacteria to expedite the discovery and progression of novel, cell-permeable antibiotics with on-target activity. (AU) | |
| FAPESP's process: | 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research |
| Grantee: | Paulo Arruda |
| Support Opportunities: | Research Grants - Research Partnership for Technological Innovation - PITE |
| FAPESP's process: | 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem) |
| Grantee: | Katlin Brauer Massirer |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 18/09475-5 - New approaches to inhibitors for protein kinases MRCKa, MRCKb AND MRCKg |
| Grantee: | Stanley Nunes Siqueira Vasconcelos |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |