Gary E. Zurenko

Besifloxacin, a Novel Fluoroquinolone, Has Broad-Spectrum In Vitro Activity against Aerobic and Anaerobic Bacteria

ABSTRACT The antibacterial spectrum of besifloxacin, a novel fluoroquinolone recently approved for treatment of ocular infections, was studied using 2,690 clinical isolates representing 40 species. Overall, besifloxacin was the most potent agent tested against gram-positive pathogens and anaerobes and was generally equivalent to comparator fluoroquinolones in activity against most gram-negative pathogens. Besifloxacin demonstrated potent, broad-spectrum activity, which was particularly notable against gram-positive and gram-negative isolates that were resistant to other fluoroquinolones and classes of antibacterial agents.

In Vitro Activity of TR-700, the Active Ingredient of the Antibacterial Prodrug TR-701, a Novel Oxazolidinone Antibacterial Agent

ABSTRACT TR-701 is the prodrug of the microbiologically active molecule TR-700, a novel orally and intravenously administered oxazolidinone antibacterial agent. The in vitro activity of TR-700 was evaluated against 1,063 bacterial clinical isolates including staphylococci, enterococci, streptococci, Moraxella catarrhalis, Haemophilus influenzae, and a variety of anaerobic bacterial species. The test strains were recent (2005 to 2008) clinical isolates from diverse U.S. (80%) and non-U.S. (20%) sites. MIC assays were conducted using reference broth microdilution and agar dilution methods with the principal comparators linezolid and vancomycin. TR-700 was four- to eightfold more potent than linezolid against staphylococci and generally fourfold more potent against enterococci and streptococci. TR-700 was less active against M. catarrhalis and H. influenzae but was twofold more active than linezolid. Against anaerobic species, the activity of TR-700 was equivalent to or up to fourfold higher than that of linezolid. These results indicate that TR-700 is a promising new oxazolidinone antibacterial agent with greater in vitro potency than linezolid against clinically important gram-positive bacteria.

Oxazolidinones: a new class of antibacterials.

The oxazolidinones represent the first truly new class of antibacterial agents to reach the marketplace in several decades. They have a unique mechanism of action involving inhibition of the initiation step of protein synthesis and are not cross-resistant to other classes of antibiotics. The first marketed member of that class, linezolid (Zyvox), shows good efficacy with an impressive antibacterial spectrum (including activity against gram-positive organisms resistant to other drugs), and a pharmacodynamic/pharmacokinetic relationship best characterized by time above the minimum inhibitory concentration. The agent is effective by both the intravenous and oral route of administration. Although technically classified as bacteriostatic against a number of pathogens in vitro, linezolid behaves in vivo like a bactericidal antibiotic.

In Vitro Activities of Linezolid Combined with Other Antimicrobial Agents against Staphylococci, Enterococci, Pneumococci, and Selected Gram-Negative Organisms

ABSTRACT The activities of linezolid, an oxazolidinone antibacterial agent active against gram-positive organisms, alone and in combination with 35 antimicrobial agents were tested in vitro against methicillin-sensitive (n = 1 to 2 strains) and methicillin-resistant (n = 8 to 10) Staphylococcus aureus strains; vancomycin-sensitive (n = 6) and vancomycin-resistant (n = 6 to 8) Enterococcus faecalis strains; vancomycin-sensitive (n = 5) and vancomycin-resistant (n = 6) Enterococcus faecium strains; penicillin-sensitive (n = 2 to 5), penicillin-intermediate (n = 5 to 6), and penicillin-resistant (n = 5 to 6) Streptococcus pneumoniae strains; Escherichia coli (n = 6); and Klebsiella pneumoniae (n = 6). The fractional inhibitory concentration indices of linezolid in combination with other antimicrobial agents for the organisms tested were generated on checkerboard broth microdilution plates prepared by a semiautomated method. Of 1,380 organism-drug combinations, 1,369 (99.2%) combinations of linezolid with 28 antimicrobial drugs were indifferent, 9 combinations (0.65%) of linezolid with 6 drugs (amoxicillin, erythromycin, imipenem, sparfloxacin, teicoplanin, and tetracycline) were synergistic, and 2 combinations (0.15%) of linezolid with 2 drugs (ofloxacin and sparfloxacin) were antagonistic. Overall, the in vitro data demonstrated that linezolid combined with other antimicrobial agents primarily produces an indifferent response, with infrequent occurrences of synergism and antagonism.

Oxazolidinones: New antibacterial agents

The oxazolidinones are a new chemical class of synthetic antibacterial agents that are active orally or intravenously against multidrug-resistant Gram-positive bacteria. Their unique mechanism of action and activity against bacteria that pose therapeutic problems in hospital and community treatments make them promising candidates for antimicrobial agents.

Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors

ABSTRACT QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (−)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the β subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

Oxazolidinone antibacterial agents: development of the clinical candidates eperezolid and linezolid

Antimicrobial resistance is a significant nosocomial problem and is of increasing importance in community-acquired infections. One approach for overcoming resistance is the discovery and development of agents with new mechanisms of action. The oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. Eperezolid and linezolid are two novel analogues that have demonstrated a variety of positive attributes. These agents inhibit many clinically-significant bacterial species both in vitro and in animal models of human infection. Furthermore they have oral bioavailability, and are well tolerated in humans at doses which produce plasma concentrations in excess of the levels predicted to be necessary for efficacy. In this review, we discuss the key information from the literature that supports the Phase II development of linezolid.

3-Arylpiperidines as potentiators of existing antibacterial agents

Important resistance patterns in Gram-negative pathogens include active efflux of antibiotics out of the cell via a cellular pump and decreased membrane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC(50) approximately 90 microM. This report details the evaluation of the tether length, aryl substitution and the importance of the fluorine on antibiotic accumulation. Evaluation of various tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumulation and the defluorinated analogue 17 is equally potent to the original lead 1.

Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs <or=0.5-1 microg/mL and moderate Gram-negative activity with MICs=2-8 microg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED(50)=1.9 mg/kg. Beta-substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10alpha. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of <or= 0.06-0.25 microg/mL against Gram-positive pathogens and with MICs of 1 microg/mL against fastidious Gram-negative pathogens.

Serum inhibitory titers and serum bactericidal titers for human subjects receiving multiple doses of the antibacterial oxazolidinones eperezolid and linezolid

In Phase I trials subjects received multiple doses of eperezolid (PNU-100592; formerly U-100592) and linezolid (PNU-100766; formerly U-100766), and steady-state samples were drawn at the projected peak and trough timepoints. Serum inhibitory titer and serum bactericidal titer values were determined using single strains of Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Serum inhibitory titer values generally correlated with drug concentration in serum and inherent organism susceptibility. Against S. aureus and E. faecalis sera from patients dosed with either drug were generally inhibitory at the peak timepoint, but at trough only linezolid exhibited a persistent effect. No bactericidal activity was seen for either drug against S. aureus or E. faecalis. The sera from patients dosed with either drug exhibited inhibition of S. pneumoniae at peak and trough. Bactericidal activity was seen against S. pneumoniae for both drugs at peak time and at trough for many of the sera for patients on the higher dose regimens. The results demonstrated that the sera from most human subjects dosed with eperezolid or linezolid were inhibitory to S. aureus and E. faecalis and S. pneumoniae and that many of the samples exhibited bactericidal activity for S. pneumoniae.