Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Eidam, O.; Romagnoli, Chiara; Dalmasso, Guillaume; Barelier, Sarah; Caselli, Emilia; Bonnet, Richard; Shoichet, Brian K.; Prati, Fabio

doi:10.1073/pnas.1208337109

Cited by 68 publications

(82 citation statements)

References 41 publications

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“…Often this reflected binding of the ligands on the surface of their proteins, allowing the ligand to grow into unfilled areas of the site and solvent (35)(36)(37)(38)(39). In the case of FabI, the enzyme responds to a series of six side-chain elongations of diphenyl ethers with a smooth shift of Ile207 and 0.5-0.9 Å movements of Tyr147 and Val201 (40) (SI Appendix, Fig.…”

Section: Conformations In Other Lysozyme Cavities Recapitulate the Threementioning

confidence: 99%

Homologous ligands accommodated by discrete conformations of a buried cavity

Merski

Fischer

Balius

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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114

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Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design.

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Section: Conformations In Other Lysozyme Cavities Recapitulate the Threementioning

confidence: 99%

Homologous ligands accommodated by discrete conformations of a buried cavity

Merski

Fischer

Balius

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

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“…The strategy here lies in the ability to identify multiple small molecules with favorable ␤-lactamase binding properties and then to apply structural and chemical information to combine the components into drug leads. In this regard, FBLD is used to refine the highest-affinity boronates with the aim of yielding compounds with significant in vivo antimicrobial activity, as previous generations of boronates have demonstrated favorable in vitro kinetics but failed to improve susceptibility (e.g., affinities in the nM range but poor MICs) (59). Examination of binding models using FBLD revealed subtle changes such as reorientation of functional groups and ring structures that improved affinity by 500-fold.…”

Section: Boronic Acid ␤-Lactamase Inhibitorsmentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

266

179

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As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing ␤-lactamase enzymes to this serious clinical problem. This review highlights recent advances in ␤-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the ␤-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new ␤-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner ␤-lactam and dosing regimens for these promising agents. This "renaissance" of ␤-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

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“…Such an approach has led to several potent inhibitor compounds (15,16). Recently, the BATSI S02030 ( Fig.…”

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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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Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Cited by 68 publications

References 41 publications

Homologous ligands accommodated by discrete conformations of a buried cavity

Homologous ligands accommodated by discrete conformations of a buried cavity

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

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

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