Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases

Sj, Hecker; Reddy, K. Rajender; Totrov, Maxim; Gc, Hirst; Lomovskaya, Olga; Dc, Griffith; King, Paula; Tsivkovski, Ruslan; D, Sun; Sabet, Mojgan; Tarazi, Ziad; Mc, Clifton; Atkins, Kateri; Raymond, Amy; Kt, Potts; Abendroth, Jan; Boyer, SH; Js, Loutit; Ee, Morgan; Durso, Stephanie; Mn, Dudley

doi:10.1021/acs.jmedchem.5b00127

Cited by 354 publications

(355 citation statements)

References 30 publications

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“…The minor difference in IC 50 could in part be attributed to S02030's ability to have stacking interactions with large aromatic residues, e.g., W105, in KPC-2, whereas such an interaction is not observed in SHV-1. It is interesting that a somewhat similar boronic acid inhibitor, RPX7009, has an amide-thiophene moiety yet a different carboxylcontaining moiety (33). The RPX7009 structure complexed to a different class A ␤-lactamase, CTX-M-15, revealed an orientation of the inhibitor generating similar active interactions by its amidethiophene moieties and carboxyl group (33).…”

Section: Resultsmentioning

confidence: 99%

Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

Nguyen

Krishnan

Rojas

et al. 2016

Antimicrob Agents Chemother

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Resistance to expanded-spectrum cephalosporins and carbapenems has rendered certain strains of Klebsiella pneumoniae the most problematic pathogens infecting patients in the hospital and community. This broad-spectrum resistance to ␤-lactamases emerges in part via the expression of KPC-2 and SHV-1 ␤-lactamases and variants thereof. KPC-2 carbapenemase is particularly worrisome, as the genetic determinant encoding this ␤-lactamase is rapidly spread via plasmids. Moreover, KPC-2, a class A enzyme, is difficult to inhibit with mechanism-based inactivators (e.g., clavulanate). In order to develop new ␤-lactamase inhibitors (BLIs) to add to the limited available armamentarium that can inhibit KPC-2, we have structurally probed the boronic acid transition state analog S02030 for its inhibition of KPC-2 and SHV-1. S02030 contains a boronic acid, a thiophene, and a carboxyl triazole moiety. We present here the 1.54-and 1.87-Å resolution crystal structures of S02030 bound to SHV-1 and KPC-2 ␤-lactamases, respectively, as well as a comparative analysis of the S02030 binding modes, including a previously determined S02030 class C ADC-7 ␤-lactamase complex. S02030 is able to inhibit vastly different serine ␤-lactamases by interacting with the conserved features of these active sites, which includes (i) forming the bond with catalytic serine via the boron atom, (ii) positioning one of the boronic acid oxygens in the oxyanion hole, and (iii) utilizing its amide moiety to make conserved interactions across the width of the active site. In addition, S02030 is able to overcome more distantly located structural differences between the ␤-lactamases. This unique feature is achieved by repositioning the more polar carboxyl-triazole moiety, generated by click chemistry, to create polar interactions as well as reorient the more hydrophobic thiophene moiety. The former is aided by the unusual polar nature of the triazole ring, allowing it to potentially form a unique COH. . .O 2.9-Å hydrogen bond with S130 in KPC-2.

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Section: Resultsmentioning

confidence: 99%

Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

Nguyen

Krishnan

Rojas

et al. 2016

Antimicrob Agents Chemother

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show abstract

“…The boronic acid inhibitor RPX7009 (Table 6) represents another novel class of synthetic non-b-lactam b-lactamase inhibitors (Hecker et al 2015), although boronic acids have been known for many years to be effective inhibitors of serine b-lactamases (Kiener and Waley 1978). Despite the inhibitory activity of RPX7009 against many groups of serine b-lactamases (Hecker et al 2015), it is being developed in combination with meropenem to target pathogens producing serine carbapenemases (Lapuebla et al 2015).…”

Section: B-lactamase Inhibitorsmentioning

confidence: 99%

“…Despite the inhibitory activity of RPX7009 against many groups of serine b-lactamases (Hecker et al 2015), it is being developed in combination with meropenem to target pathogens producing serine carbapenemases (Lapuebla et al 2015).…”

Section: B-lactamase Inhibitorsmentioning

confidence: 99%

β-Lactams and β-Lactamase Inhibitors: An Overview

Bush

Bradford

2016

Cold Spring Harb Perspect Med

835

587

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b-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related b-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of b-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to b-lactams is primarily because of bacterially produced b-lactamase enzymes that hydrolyze the b-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum b-lactamase inhibitors that work against many problematic b-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of b-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

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“…From this first hit, a large variety of compounds with varying N‐acyl substituents were synthesized. The 2‐thienyl acetyl analogue RPX7009 ( 58 ) was found to be the most potent derivative, while also displaying a broad spectrum of inhibition and high selectivity 181. RPX7009 is a broad‐spectrum inhibitor, notably restoring the activity of carbapenems against carbapenemase‐producing K. pneumoniae strains.…”

Section: β‐Lactamase Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases

Cited by 354 publications

References 30 publications

Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030

β-Lactams and β-Lactamase Inhibitors: An Overview

Targeting Antibiotic Resistance

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