ANT2681: SAR Studies Leading to the Identification of a Metallo-β-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae

Abstract

The clinical effectiveness of the important β-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address this resistance issue, multiple β-lactam/β-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.

β-lactam Resistance in Pseudomonas aeruginosa: Current Status, Future Prospects

“…Of particular significance, taniborbactam and xeruborbactam are pan-β-lactamase inhibitors that can inhibit all classes of β-lactamases, including metallo-β-lactamases which are not targeted by other inhibitors. A novel metalloβ-lactamase inhibitor ANT431 is also at a pre-clinical stage [317,318]. A number of other compounds are also under development, although how many will find their way into the clinic, and whether they will be subject to the same resistance mechanisms as existing compounds, is not yet clear [319,320].…”

Novel Specific Metallo-β-Lactamase Inhibitor ANT2681 Restores Meropenem Activity to Clinically Effective Levels against NDM-Positive Enterobacterales

“…ANT2681 is the culmination of a chemistry program designed to deliver a potent and selective NDM inhibitor. This compound shows no P450 inhibition, hERG inhibition, mammalian cytotoxicity, or genotoxicity, is selective toward other metalloenzymes ( 14 ), and was well tolerated in safety toxicology/pharmacology studies at exposures well above those necessary for efficacy ( 15 ). As the area under the concentration curve from 0 to 24 h (AUC 0–24 ) is the pharmacodynamic index driving ANT2681 efficacy ( 15 ) it should be feasible to administer an efficacious dose in combination with 2 g MEM, administered as a 3-h infusion every 8 h, which would provide coverage of CREs with MEM MICs of up to 8 μg/ml.…”

“…ANT2681 is a specific, competitive small molecule inhibitor of MBLs ( K i of 100 nM, 680 nM, and 6.3 μM versus VIM-1, VIM-2, and IMP-1, respectively; unpublished data) with particularly potent activity against NDM-1 ( K i , 40 nM) ( 13 , 14 ) and in vivo efficacy against NDM-positive CRE in murine thigh models of infection ( 15 ), which is being progressed to clinical development.…”

Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D)

“…These compounds are mainly able to efficiently inhibit SBLs, including carbapenemases, of class A, C and sometimes D, but generally do not inhibit MBLs (class B). In parallel, continuous efforts for the development of efficient MBL inhibitors [22,23] have recently led to the identification of promising molecules that can bind to zinc atoms of the active site of MBLs, such as thiadiazole [24] or thiols [25,26] -including the clinically available antihypertensive agent L-captopril [27] -, aspergillomarasmine A [28] and other iminodiacetic acids, [29,30] rhodanines [31] and their thienolate derivatives [32] or heteroaryl compounds [33,34] such as ANT2681 [35] or ANT431 [36] (Figure 1c). Yet there is still no MBL inhibitor available for clinical use.…”