Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-ß-lactamases.

Despite major advances in the ß-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a ß-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.

Methodology for Monobactam Diversification: Syntheses and Studies of 4-Thiomethyl Substituted ß-Lactams with Activity against Gram-Negative Bacteria, Including Carbapenemase Producing Acinetobacter baumannii.

Bromine induced lactamization of vinyl acetohydroxamates facilitated syntheses of monocyclic ß-lactams suitable for incorporation of a thiomethyl and extended functionality at the C(4) position. Elaboration of the resulting substituted N-hydroxy-2-azetidinones allowed incorporation of functionalized α-amino substituents appropriate for enhancement of antibiotic activity. Evaluation of antibacterial activity against a panel of Gram-positive and Gram-negative bacteria revealed structure-activity relationships (SAR) and identification of potent new monobactam antibiotics. The corresponding bis-catechol conjugate, 42, has excellent activity against Gram-negative bacteria including carbapenemase and carbacephalosporinase producing strains of Acinetobacter baumannii, which have been listed by the WHO as being of critical concern worldwide.

Quinazolinone-based fungal efflux pump inhibitors. Part 1: Discovery of an (N-methylpiperazine)-containing derivative with activity in clinically relevant Candida spp.

The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.

Prodrugs of cephalosporin RWJ-333441 (MC-04,546) with improved aqueous solubility.

To improve the aqueous solubility of anti-methicillin-resistant Staphylococcus aureus cephalosporin RWJ-333441 for parenteral administration, acyl derivatives of the C-3 primary amino group were prepared and evaluated for solubility, cleavage in serum in vitro, and conversion to RWJ-333441 in vivo. Improved solubility at physiologic pH values and release of RWJ-333441 in vitro and in vivo were observed for several prodrugs, including the aspartate derivative RWJ-333442.

Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in 3-(heteroarylthio)cephems. Discovery of RWJ-333441 (MC-04,546).

SAR studies in a series of related 3-(heteroarylthio)cephems determined that a relatively high chemical reactivity of the beta-lactam ring, modulated by electronic effects of substituents at C-3 and C-7, is necessary to achieve high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA). Such high reactivity results in lowered hydrolytic stability and concomitantly increases susceptibility to beta-lactam ring opening mediated by serum enzymes. Therefore, optimization of anti-MRSA activity versus stability toward serum-mediated degradation required a fine balance of substituent effects. Serum stability studies (measured as percentage of parent drug degraded after 60 min incubation) revealed up to 80-fold difference in degradation rate in a series of closely related (3-heteroarylthio)cephems. Of the compounds evaluated, RWJ-333441 (MC-04,546) possessed the best balance of serum stability (6% degradation after 60 min incubation) and in vitro activity versus MRSA (S. aureus COL MIC=1 microgram/mL). Accordingly, RWJ-333441 displayed excellent in vivo efficacy versus methicillin-susceptible Staphylococcus aureus (MSSA, ED(50)=0.39 mg/kg in mouse sepsis model with S. aureus Smith) and good pharmacokinetic properties in the rat (Cl(total)=0.39 L/h/kg).

Novel cephalosporins for the treatment of MRSA infections.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are among the most difficult to treat, Efforts toward the development of cephalosporin antimicrobial agents with activity against MRSA have been ongoing for the last decade. In spite of advancement of several potential drugs into clinical trials no such drugs are available for anti-MRSA therapy yet. The recent emergence of MRSA strains resistant to vancomycin, which is the treatment of choice for MRSA infection, has made the clinical need for new effective drugs even more pressing. In the present review structure-activity relationships are discussed with an emphasis on anti-MRSA activity, pharmacokinetics and efficacy in animal models. Clinical trial status of promising drug candidates is also provided where available.