id8b00011_si_001.pdf (2.25 MB)
Vancomycin Analogue Restores Meropenem Activity against NDM‑1 Gram-Negative Pathogens
journal contribution
posted on 2018-05-04, 00:00 authored by Venkateswarlu Yarlagadda, Paramita Sarkar, Sandip Samaddar, Goutham Belagula Manjunath, Susweta Das Mitra, Krishnamoorthy Paramanandham, Bibek Ranjan Shome, Jayanta HaldarNew Delhi metallo-β-lactamase-1
(NDM-1) is the major contributor to the emergence of carbapenem resistance
in Gram-negative pathogens (GNPs) and has caused many clinically available
β-lactam antibiotics to become obsolete. A clinically approved
inhibitor of metallo-β-lactamase (MBL) that could restore the
activity of carbapenems against resistant GNPs has not yet been found,
making NDM-1 a serious threat to human health. Here, we have rationally
developed an inhibitor for the NDM-1 enzyme, which has the ability
to penetrate the outer membrane of GNPs and inactivate the enzyme
by depleting the metal ion (Zn2+) from the active site.
The inhibitor reinstated the activity of meropenem against NDM-1 producing
clinical isolates of GNPs like Klebsiella pneumoniae and Escherichia coli. Further, the inhibitor efficiently
restored meropenem activity against NDM-1 producing K. pneumoniae in a murine sepsis infection model. These findings demonstrate that
a combination of the present inhibitor and meropenem has high potential
to be translated clinically to combat carbapenem-resistant GNPs.