Exploring the potential of boronic acids as inhibitors of OXA‐24/40 β‐lactamase

Abstract

b-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to b-lactams is the expression of b-lactamase enzymes. To overcome b-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for b-lactamases also contain the characteristic b-lactam ring, making them susceptible to resistance mechanisms employed by bacteria. This presents a critical need for novel, non-b-lactam inhibitors that can circumvent these resistance mechanisms. The carbapenemhydrolyzing class D b-lactamases (CHDLs) are of particular concern, given that they efficiently hydrolyze potent carbapenem antibiotics. Unfortunately, these enzymes are not inhibited by clinically available b-lactamase inhibitors, nor are they effectively inhibited by the newest, non-b-lactam inhibitor, avibactam. Boronic acids are known transition state analog inhibitors of class A and C blactamases, and are not extensively characterized as inhibitors of class D b-lactamases. Importantly, boronic acids provide a novel way to potentially inhibit class D b-lactamases. Sixteen boronic acids were selected and tested for inhibition of the CHDL OXA-24/40. Several compounds were identified as effective inhibitors of OXA-24/40, with K i values as low as 5 lM. The X-ray crystal structures of OXA-24/40 in complex with BA3, BA4, BA8, and BA16 were determined and revealed the importance of interactions with hydrophobic residues Tyr112 and Trp115. These boronic acids serve as progenitors in optimization efforts of a novel series of inhibitors for class D b-lactamases.

Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches

“…S02030 is very potent at inhibiting β-lactamases observed in Klebsiella pneumoniae and E. coli species. Developing boronic acid β-lactamase inhibitors is a promising approach as has been shown for a number of different β-lactamases (Tondi et al, 2010 , 2014 ; Powers et al, 2014 ; Bouza et al, 2017 ; Werner et al, 2017 ; Caselli et al, 2018 ).…”

Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition

“…11 Boronate-based compounds have long been known as β-lactamase inhibitors. [11][12][13][14][15][16] In 2017 the combination of vaborbactam (a monocyclic boronate, Figure 1B) with meropenem (Vabomere ® ) was clinically approved to treat complicated UTIs. 5,17 Vaborbactam is particularly potent against the SBL KPC-2, but is not active against class D SBLs, 18 and only moderately inhibits some MBLs.…”

Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC‐2: A Step against Bacterial Resistance

“…In the de novo BL inhibitors scenario, boronic acid derivatives play an interesting role: they possess a non‐β‐lactam moiety and act as competitive inhibitors of BLs, covalently, but reversibly, binding the catalytic serine of BLs belonging to classes A, C, and D . Very recently, boronic acids were also reported to inhibit zinc‐dependent BLs, opening the way for the development of dual‐action inhibitors .…”

“…ever,s lowly hydrolyzed by KPC-2, which suggests peculiarities in the catalytic mechanism for class Acarbapenemase. [15] In the de novo BL inhibitors scenario,b oronic acid derivatives play an interesting role:t hey possess an on-b-lactam moiety and act as competitive inhibitors of BLs, covalently,b ut reversibly,b inding the catalytic serine of BLs belongingt o classes A, C, and D. [16][17][18][19][20][21] Very recently, boronic acids were also reportedt oi nhibit zinc-dependent BLs, openingt he way for the development of dual-actioni nhibitors. [22,23] RPX7009, a highly potent inhibitoro fK PC, is currently in development.…”