Jamese J. Hilliard

Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity : Pharmacophore identification based on the screening hit closantel

This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.

Synthesis and topoisomerase inhibitory activities of novel aza-analogues of flavones

Abstract Aseries of aza-flavones (3-hydroxy-2-phenyl-4-quinolones) were designed and synthesized as inhibitors of bacterial DNA-gyrase and mammalian topoisomerase II. Structure activity relationships of the compounds against each of the enzymes are discussed.

Synthesis and antibacterial activity of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones

A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon-carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.

Identification of a Dithiazoline Inhibitor of Escherichia coli l,d-Carboxypeptidase A

ABSTRACT The enzyme l,d-carboxypeptidase A is involved in the recycling of bacterial peptidoglycan and is essential in Escherichia coli during stationary phase. By high-throughput screening, we have identified a dithiazoline inhibitor of the enzyme with a 50% inhibitory concentration of 3 μM. The inhibitor appeared to cause lysis of E. coli during stationary phase, behavior that is similar to a previously described deletion mutant of l,d-carboxypeptidase A (M. F. Templin, A. Ursinus, and J.-V. Holtje, EMBO J. 18:4108-4117, 1999). As much as a one-log drop in CFU in stationary phase was observed upon treatment of E. coli with the inhibitor, and the amount of intracellular tetrapeptide substrate increased by approximately 33%, consistent with inhibition of the enzyme within bacterial cells. Stationary-phase targets such as l,d-carboxypeptidase A are largely underrepresented as targets of the antibiotic armamentarium but provide potential opportunities to interfere with bacterial growth and persistence.

Comparative Effects of Carbapenems on Bacterial Load and Host Immune Response in a Klebsiella pneumoniae Murine Pneumonia Model

ABSTRACT Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log10 CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log10 CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log10 CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.

DNA gyrase inhibitory activity of ellagic acid derivatives

Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.