Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable ß-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.

A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. The increasing emergence of ß-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing ß-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum ß-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.

Microbiological Characterization of VNRX-5236, a Broad-Spectrum ß-Lactamase Inhibitor for Rescue of the Orally Bioavailable Cephalosporin Ceftibuten as a Carbapenem-Sparing Agent against Strains of Enterobacterales Expressing Extended-Spectrum ß-Lactamases and Serine Carbapenemases.

There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid ß-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended-spectrum ß-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine ß-lactamases, with inactivation efficiencies on the order of 104 M-1 · sec-1, and prolonged active site residence times (t1/2, 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 µg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D ß-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90, 0.25 µg/ml), KPCs (MIC90, 1 µg/ml), class C cephalosporinases (MIC90, 1 µg/ml), and OXA-48-type carbapenemases (MIC90, 1 µg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo, whereas ceftibuten alone was ineffective (50% effective dose [ED50], >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED50, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-ß-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa.

As shifts in the epidemiology of ß-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved ß-lactam (BL)-ß-lactamase inhibitor (BLI) combinations address widespread serine ß-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-ß-lactamases (KPC, OXA-48) or clinically important metallo-ß-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by ß-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki ) values ranging from 0.019 to 0.081 µM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 µg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

Prospective evaluation of feasibility and electrophysiologic and echocardiographic characteristics of left bundle branch area pacing.

BACKGROUND: His bundle pacing (HBP) is the most physiologic form of pacing but associated with higher thresholds and lower success in patients with His-Purkinje conduction disease. Recent reports have described transvenous left bundle branch area pacing (LBBAP). OBJECTIVE: We aimed to prospectively evaluate the feasibility and the electrophysiologic and echocardiographic characteristics of LBBAP. METHODS: Patients requiring pacing for bradycardia or heart failure indications (failed left ventricular [LV] lead) were prospectively enrolled. LBBAP was performed with a Medtronic 3830 lead. Presence of left bundle branch (LBB) potential, paced QRS morphology/duration, and peak LV activation time (pLVAT) were recorded at implant. Pacing threshold and sensing was assessed at implant and follow-up. Echocardiography was performed to assess the approximate lead location and impact on tricuspid valve function. RESULTS: LBBAP was successful in 93 of 100 (93%) patients. Mean age was 75 ± 13 years; men 69%, left bundle branch block 24%, right bundle branch block 25%, intraventricular conduction defect 8%. Indications for pacing were atrioventricular (AV) block 54%, sinus node dysfunction 23%, AV node ablation 7%, cardiac resynchronization therapy 11%, HBP lead failure 7%. Baseline QRS duration was 133 ± 35 ms. Paced QRS duration was 136 ± 17 ms. LBB potentials were observed in 63 patients with left bundle branch - ventricle (LBB-V) interval of 27 ± 6 ms. pLVAT was 75 ± 16 ms. Pacing threshold at implant was 0.6 ± 0.4 V @ 0.5 ms and R waves were 10 ± 6 mV and remained stable at median follow-up of 3 months. The lead depth in the septum was approximately 1.4 ± 0.23 cm. CONCLUSIONS: LBBAP was feasible in a high percentage of patients with low thresholds during acute follow-up. HBP and LBBAP may significantly increase the overall success of physiologic pacing.