Ten Years with New Delhi Metallo-β-lactamase-1 (NDM-1): From Structural Insights to Inhibitor Design

Abstract

The worldwide emergence of New Delhi metallo-β-lactamase-1 (NDM-1) as a carbapenemase able to hydrolyze nearly all available β-lactam antibiotics has characterized the past decade, endangering efficacious antibacterial treatments. No inhibitors for NDM-1 are available in therapy, nor are promising compounds in the pipeline for future NDM-1 inhibitors. We report the studies dedicated to the design and development of effective NDM-1 inhibitors. The discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize β-lactam antibiotics. A structural analysis of NDM-1 mechanism of action based on selected X-ray complexes is also reported: the intrinsic flexibility of the binding site and the comparison between penicillin/cephalosporin and carbapenem mechanisms of hydrolysis are evaluated. Despite the valuable progress in terms of structural and mechanistic information, the design of a potent NDM-1 inhibitor to be introduced in therapy remains challenging. Certainly, only the deep knowledge of NDM-1 architecture and of the variable mechanism of action that NDM-1 employs against different classes of substrates could orient a successful drug discovery campaign.

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

“…[26,27] A survey of current NDM-1 inhibitors reveals al arge portion of inhibitors bear ac arboxylic acid motif. [25,26] In line with this, our lab previouslyu sed af ragment-based drugd iscovery( FBDD) approacht oi dentify dipicolinica cid (DPA) as al ead metalbinding pharmacophore (MBP) for NDM-1i nhibitor development. [28] Derivatization of DPAw as performed to obtain 4-(3aminophenyl)pyridine-2,6-dicarboxylic acid ( Figure 1) as a highly selective inhibitor for NDM-1 (IMP-1 and VIM-2) that inhibits by forming as table NDM-1:Zn II :inhibitor ternary complex.…”

“…[22][23][24] Unfortunately,e ven with the rapid spread of the bla NDM gene and the evolution of NDM variants,l ittle advancement has been made in inhibitor development. There are currently % 525 inhibitors reported in literature( representative structures shown in Figure 1), [25] but many inhibitors share similars tructuralf eatures and none have progressed to clinicalt rials. The flexible active site of NDM-1, the diversity of relatedM BLs, al ack of understanding for inhibition mechanisms, and misinterpretation of structural data have all contributed to delayedi nhibitor development.…”

“…[4,14,21] Some NDM variants exhibit an increasei nt hermal stability, Zn II affinity,a nd mononuclear Zn II activity that may provide an evolutionary advantage when Zn II availability is low. There are currently % 525 inhibitors reported in literature( representative structures shown in Figure 1), [25] but many inhibitors share similars tructuralf eatures and none have progressed to clinicalt rials. There are currently % 525 inhibitors reported in literature( representative structures shown in Figure 1), [25] but many inhibitors share similars tructuralf eatures and none have progressed to clinicalt rials.…”

“…There are currently % 525 inhibitors reported in literature( representative structures shown in Figure 1), [25] but many inhibitors share similars tructuralf eatures and none have progressed to clinicalt rials. [25,26] In line with this, our lab previouslyu sed af ragment-based drugd iscovery( FBDD) approacht oi dentify dipicolinica cid (DPA) as al ead metalbinding pharmacophore (MBP) for NDM-1i nhibitor development. [26,27] A survey of current NDM-1 inhibitors reveals al arge portion of inhibitors bear ac arboxylic acid motif.…”

Critical analysis of antibacterial agents in clinical development

“…Boronate BLIs lack an intrinsic effect but have evolved into BLIs with a wider inhibitory spectrum to include some MBLs such as NDM and VIM (taniborbactam and the preclin ical BLI QPX7728). Given that β lactamases are mecha nistically and structurally distinct, finding a BLI that is equally effective against all classes and relevant enzymes remains difficult 33,34 .…”