Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

Zhongjie Liang, Lianchun Li, Yuanyuan Wang, Limin Chen, Xiangqian Kong, Yao Hong, Lefu Lan, Mingyue Zheng, Cai Guang-Yang, Hong Liu, Xu Shen, Cheng Luo, Keqin Kathy Li, Kaixian Chen, Hualiang Jiang

Abstract
The New Delhi Metallo-b-lactamase (NDM-1) was first reported in 2009 in a Swedish patient. A recent study reported that
Klebsiella pneumonia NDM-1 positive strain or Escherichia coli NDM-1 positive strain was highly resistant to all antibiotics
tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now
becomes potentially a major global health threat. In this study, we performed modeling studies to obtain its 3D structure
and NDM-1/antibiotics complex. It revealed that the hydrolytic mechanisms are highly conserved. In addition, the detailed
analysis indicates that the more flexible and hydrophobic loop1, together with the evolution of more positive-charged
loop2 leads to NDM-1 positive strain more potent and extensive in antibiotics resistance compared with other MBLs.
Furthermore, through biological experiments, we revealed the molecular basis for antibiotics catalysis of NDM-1 on the
enzymatic level. We found that NDM-1 enzyme was highly potent to degrade carbapenem antibiotics, while mostly
susceptible to tigecycline, which had the ability to slow down the hydrolysis velocity of meropenem by NDM-1. Meanwhile,
the mutagenesis experiments, including D124A, C208A, K211A and K211E, which displayed down-regulation on
meropenem catalysis, proved the accuracy of our model. At present, there are no effective antibiotics against NDM-1
positive pathogen. Our study will provide clues to investigate the molecular basis of extended antibiotics resistance of
NDM-1 and then accelerate the search for new antibiotics against NDM-1 positive strain in clinical studies.