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A series of vancomycin derivatives alkylated at the N-terminus amine were synthesized, including those that contain quaternary trimethylammonium salts either directly at the terminal amine site or with an intervening three-carbon spacer. The examination of their properties provides important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogues through an added mechanism of action. The N-terminus modifications disclosed herein were well-tolerated, minimally altering model ligand binding affinities (d-Ala-d-Ala) and antimicrobial activity, but did not induce membrane permeabilization that was observed with a similar C-terminus modification. The results indicate that our earlier observations with the C-terminus modification are sensitive to the site as well as structure of the trimethylammonium salt modification and are not simply the result of nonspecific effects derived from introduction of a cationic charge.

New 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 (Zn 2+ ) 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.