Design, Synthesis and Biological Evaluation of Conjugates of 3-<i>O</i>-Descladinose-azithromycin and Nucleobases against rRNA A2058G- or A2059G-Mutated Strains
Xiaotian Lian,
Wentian Liu,
Bingzhi Fan,
Mingjia Yu,
Jianhua Liang
Affiliations
Xiaotian Lian
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
Wentian Liu
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
Bingzhi Fan
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
Mingjia Yu
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
Jianhua Liang
Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
Structurally unrelated antibiotics MLSB (macrolide-lincosamide-streptogramin B) compromised with clinically resistant pathogens because of the cross-resistance resulting from the structural modification of rRNA A2058. The structure–activity relationships of a novel 3-O-descladinose azithromycin chemotype conjugating with nucleobases were fully explored with the aid of engineered E. coli SQ110DTC and SQ110LPTD. The conjugates of macrolides with nucleobases, especially adenine, displayed antibacterial superiority over telithromycin, azithromycin and clindamycin against rRNA A2058/2059-mutated engineered E. coli strains at the cost of lowering permeability and increasing vulnerability to efflux proteins against clinical isolates.
