According to WHO, drug-resistant bacteria has posed great threat to human health and induced urgent needs for new antibiotics. Infections caused by multidrug-resistant (MDR) Gram-negative pathogens call for both effective and safe therapeutic drugs. But the clinical pipeline for new agents is very limited.

The reduction of outer membrane permeability represents a major mechanism of resistance of Gram-negative pathogens. One strategy to circumvent the penetration issue is to exploit the iron uptake pathway of Gram-negative pathogens by conjugating a siderophore to an antibiotic.

Recently, a number of novel siderophore-conjugated monocyclic β-lactams have been studied, and the most progressed compound BAL30072 has been investigated in phase I clinical studies. It exhibits potent activities against MDR P. aeruginosa and A.baumannii, but ineffectively against some Enterobacteriaceae, especially for K.pneumonia, which would limit its application in the treatment of associated infections.

On the basis of the structure of BAL30072, Prof. YANG Yushe’s lab at Shanghai Institute of Materia Medica (SIMM), CAS has designed and synthesized a series of novel siderophore-conjugated monocyclic β-lactams, and investigated their structure-activity/ pharmacokinetic relationships comprehensively.

The resulting compound 12c (Figure，YT-14), showed potent in vitro antibacterial activity against some MDR bacteria, such as A. baumannii (OXA23), K. pneumoniae (KPC-2), P. aeruginosa (IMP4) and extended-spectrum-β-lactamase-producing E. coli (ESBLs). In a murine systemic infection model with MDR K. pneumoniae (KPC-2), compound YT-14 showed excellent in vivo protection efficacy.

Through thorough structural modification of BAL30072, this study has obtained the promising drug candidate YT-14, which could be used for the treatment of serious infections caused by MDR Gram-negative pathogens. The research result has been published in Journal of Medicinal Chemistry.

The research was completed by Ph.D. candidate TAN Liang and graduate student TAO Yunliang under the co-instruction of Prof. YANG Yushe (SIMM) and Prof. WANG Haidong (Jiaxing University).

This work was supported by the National Natural Science Foundation of China and the Drug Independent Development Task from SIMM.

Article link: http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01261 

Figure: Antibacterial activity of compound 12c（Source by SIMM） 

keywords: 

Bacterial resistance; Gram-negative pathogens; siderophore-conjugated antibiotic; antibacterial activity 

Contact: 

Prof. YANG Yushe 

Email: ysyang@simm.ac.cn 

(Credit: TAN Liang ; Editor : PAN Peihua)