scholarly journals Comparative Antimicrobial Characterization of LBM415 (NVP PDF-713), a New Peptide Deformylase Inhibitor of Clinical Importance

2005 ◽  
Vol 49 (4) ◽  
pp. 1468-1476 ◽  
Author(s):  
Thomas R. Fritsche ◽  
Helio S. Sader ◽  
Roy Cleeland ◽  
Ronald N. Jones
Keyword(s):  
Legionella Pneumophila ◽  
Antimicrobial Agents ◽  
Bacterial Species ◽  
Clinical Importance ◽  
Single Step ◽  
Peptide Deformylase ◽  
Gram Positive ◽  
Serious Infections ◽  
Tract Disease

ABSTRACT LBM415 (NVP PDF-713) is the first member of the peptide deformylase (PDF) inhibitor class being developed for clinical trials as a parenteral and oral agent for treatment of community-acquired respiratory tract disease and serious infections caused by antimicrobial-resistant gram-positive cocci. In this study susceptibility testing results from 1,306 recent clinical isolates selected to overrepresent resistance trends among the species were summarized. All staphylococci (153 strains; MIC at which 90% of isolates were inhibited [MIC90], 2 μg/ml), Streptococcus pneumoniae (170 strains; MIC90, 1 μg/ml), other streptococci (150 strains; MIC90, 1 μg/ml), enterococci (104 strains; MIC90, 4 μg/ml), Moraxella catarrhalis (103 strains; MIC90, 0.5 μg/ml), and Legionella pneumophila (50 strains; MIC90, 0.12 μg/ml) were inhibited at ≤8 μg of LBM415/ml, as were 97% of Haemophilus influenzae isolates (300 strains; MIC90, 4 to 8 μg/ml). Among other bacterial groups, 100% of gram-positive and -negative anaerobes, including 22 Bacteroides spp. strains (31 strains total; MIC90, 1 μg/ml), were inhibited by ≤4 μg/ml, whereas Enterobacteriaceae (112 strains) and most nonfermentative bacilli (107 strains) were not inhibited at readily achievable concentrations. The compound was found to have a dominantly bacteriostatic action, and spontaneous single-step mutational rates occurred at low levels (10−6 to <10−8). Drug interaction studies failed to identify any class-specific synergistic interactions, nor were antagonistic interactions observed. Variations in broth and agar MIC test conditions demonstrated that, whereas the agar-based method trended towards a 1-log2 dilution-higher MIC than the broth method and was inoculum dependent, other variations in incubation environment, medium supplements, pH, or calcium concentration had little influence on LBM415 MIC results. Use of the efflux inhibitor phe-arg-β-naphthylamide showed an average of 1 log2 dilution decrease in H. influenzae MICs, demonstrating the contribution of efflux pumps in influencing susceptibility to PDF inhibitors. The in vitro activity of LBM415 against targeted bacterial species, including resistant subsets, and other laboratory characteristics of this novel compound demonstrate the potential of PDF inhibitors as a new class of antimicrobial agents.

scholarly journals In VitroAntibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria

2014 ◽  
Vol 59 (1) ◽  
pp. 467-474 ◽  
Author(s):  
Michael D. Huband ◽  
Patricia A. Bradford ◽  
Linda G. Otterson ◽  
Gregory S. Basarab ◽  
Amy C. Kutschke ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Legionella Pneumophila ◽  
Bacterial Species ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Topoisomerase Inhibitor

ABSTRACTAZD0914 is a new spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor with potentin vitroantibacterial activity against key Gram-positive (Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae,Streptococcus pyogenes, andStreptococcus agalactiae), fastidious Gram-negative (Haemophilus influenzaeandNeisseria gonorrhoeae), atypical (Legionella pneumophila), and anaerobic (Clostridium difficile) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance inS. aureus, and if mutants were obtained, the mutations mapped togyrB. Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, β-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration andin vitrotime-kill studies. Inin vitrocheckerboard/synergy testing with 17 comparator antibacterials, only additivity/indifference was observed. The potentin vitroantibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.

scholarly journals In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups

2007 ◽  
Vol 51 (4) ◽  
pp. 1191-1201 ◽  
Author(s):  
Michael D. Huband ◽  
Michael A. Cohen ◽  
Margaret Zurack ◽  
Debra L. Hanna ◽  
Laura A. Skerlos ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Legionella Pneumophila ◽  
Bacterial Species ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Topoisomerase Inhibitors ◽  
Gram Positive ◽  
Resistant Mutants

ABSTRACT PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (μg/ml) for PD 0305970 capable of inhibiting ≥90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50 = 3.2 mg/kg) and was 22-fold more potent than levofloxacin.

scholarly journals In Vitro, Controlling the Establishment of Xanthomonas Campestris with different Bacterial Bioagents

2016 ◽  
Vol 29 (1) ◽  
pp. 37-40
Author(s):  
Amna Ali ◽  
M Saleem Haider ◽  
Sobia Mushtaq ◽  
Ibatsam Khokhar ◽  
Irum Mukhtar ◽  
...  
Keyword(s):  
Xanthomonas Campestris ◽  
Fruits And Vegetables ◽  
Antimicrobial Agents ◽  
Bacterial Species ◽  
Bacterial Strains ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Diffusion Technique

The antimicrobial agents of bacteria isolated from different rhizosphere of fruits and vegetables soil in Lahore. Of ten species, five were gram-negative (Escherichia coli, Pseudomonas fluorescence, Klebsiella pneumoniae, Salmonella typhii, Brachybacterium faecium); other five were gram positive and identified as Bacillus farraginis, Kurthia gibsonii, Aureobacterium liquefaciens, Curtobacterium albidum, Micrococcus lylae. The antagonistic potential of bacterial strains was assessed by the well diffusion technique and results indicating varying degree of biocontrol activity against pathogenic strain of X. campestris. Out of ten bacterial species, E. coli (gram negative) and C. albidum (gram positive) showed a high prevalence of resistance with reduction of 4.2cm and 4.1cm zone diameter respectively. The minimum inhibitory volume (MIV) to two bio-agents was determined for X. campestris from range 10-100 ?L. E. coli (volume required to inhibit < 20 ?L) and C. albidum (volume required to inhibit < 40 ?L) exhibited good activity against pathogen. These results provide information on the prevalence of resistant bacterial strains with the MIV of organisms and indicate the possibility of using these bacterial species as bio-agent against X. campestris.Bangladesh J Microbiol, Volume 29, Number 1, June 2012, pp 37-40

scholarly journals Potent Sub-MIC Effect of GSK1322322 and Other Peptide Deformylase Inhibitors onIn VitroGrowth of Staphylococcus aureus

2013 ◽  
Vol 58 (1) ◽  
pp. 290-296 ◽  
Author(s):  
Deborah Butler ◽  
Dongzhao Chen ◽  
Karen O'Dwyer ◽  
Thomas Lewandowski ◽  
Kelly Aubart ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Alternative Therapy ◽  
Multidrug Resistant ◽  
Peptide Deformylase ◽  
Content Type ◽  
Inhibition Of Growth ◽  
Serious Infections ◽  
Antibacterial Target

ABSTRACTPeptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistantStaphylococcus aureus(MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can preventS. aureusin vitrogrowth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited toS. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels inStreptococcus pneumoniaeorHaemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selectedS. aureusstrains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistantS. aureus.

scholarly journals Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin α, and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

2004 ◽  
Vol 48 (3) ◽  
pp. 739-746 ◽  
Author(s):  
Peter J. Petersen ◽  
T. Z. Wang ◽  
Russell G. Dushin ◽  
Patricia A. Bradford
Keyword(s):  
Natural Product ◽  
Bactericidal Activity ◽  
Antimicrobial Agents ◽  
Marked Decrease ◽  
Gram Positive ◽  
Novel Structure ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Further Development

ABSTRACT AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin α (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC90s], 0.03 to 0.06 μg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC90s, 0.12 and 0.25 μg/ml, respectively) as well as against streptococcal strains (MIC90s, ≤ 0.008 to 0.03 μg/ml). AC98-6446 demonstrated bactericidal activity in terms of the reduction in the viable counts (>3 log10 CFU/ml) of staphylococcal and streptococcal isolates and a marked decrease in the viable counts of most enterococcal strains (from 0.2 to 2.5 log10 CFU/ml). Unlike vancomycin, which demonstrates time-dependent killing, AC98-6446 demonstrated concentration-dependent killing. The potent activity, novel structure, and bactericidal activity demonstrated by AC98-6446 make it an attractive candidate for further development.

scholarly journals In vitro susceptibility studies and detection of vancomycin resistance genes in clinical isolates of enterococci in Nagasaki, Japan

1997 ◽  
Vol 119 (2) ◽  
pp. 175-181 ◽  
Author(s):  
Y. HIRAKATA ◽  
T. YAMAGUCHI ◽  
K. IZUMIKAWA ◽  
J. MATSUDA ◽  
K. TOMONO ◽  
...  
Keyword(s):  
Resistance Genes ◽  
Antimicrobial Agents ◽  
The United States ◽  
Vancomycin Resistance ◽  
Single Step ◽  
Clinical Isolates ◽  
Glycopeptide Resistance ◽  
In Vitro Susceptibility ◽  
Enterococcus Gallinarum

Glycopeptide resistance in enterococci is now a cause of clinical concern in the United States and Europe. However, details of vancomycin resistance in enterococci in Japan have been unknown. We measured minimum inhibitory concentrations (MICs) of various antimicrobial agents for a total of 218 clinical strains of enterococci isolated in our hospital in 1995–6 in addition to 15 strains with known genotypic markers of resistance. We also screened vancomycin resistance genes using a single step multiplex-PCR.In clinical isolates, only two strains of Enterococcus gallinarum were of intermediate resistance to vancomycin (MIC, 8 μg/ml), while the others were all susceptible. Glycopeptides (vancomycin and teicoplanin) and streptogramins (RP 58500 and RPR 106972) showed potent antimicrobial effects for the isolates. In addition, ampicillin was also potent for Enterococcus faecalis, while ampicillin, minocycline and gentamicin were potent for Enterococcus avium. No vanA or vanB genes were detected, while vanC1 and vanC23 genes were detected from two and four strains, respectively. Our results suggest that incidence of VRE in Japan may be estimated as still very low at this time.

scholarly journals In Vitro Activity of Eravacycline against Gram-Positive Bacteria Isolated in Clinical Laboratories Worldwide from 2013 to 2017

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Ian Morrissey ◽  
Stephen Hawser ◽  
Sibylle H. Lob ◽  
James A. Karlowsky ◽  
Matteo Bassetti ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Microdilution Method ◽  
Clinical Laboratories ◽  
Broth Microdilution Method ◽  
Doubling Dilution

ABSTRACT Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine in vitro MIC data for isolates of Enterococcus spp. (n = 2,807), Staphylococcus spp. (n = 4,331), and Streptococcus spp. (n = 3,373) isolated primarily from respiratory, intra-abdominal, urinary, and skin specimens by clinical laboratories in 37 countries on three continents from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. There were no substantive differences (a >1-doubling-dilution increase or decrease) in eravacycline MIC90 values for different species/organism groups over time or by region. Eravacycline showed MIC50 and MIC90 results of 0.06 and 0.12 μg/ml, respectively, when tested against Staphylococcus aureus, regardless of methicillin susceptibility. The MIC90 values of eravacycline for Staphylococcus epidermidis and Staphylococcus haemolyticus were equal (0.5 μg/ml). The eravacycline MIC90s for Enterococcus faecalis and Enterococcus faecium were 0.06 μg/ml and were within 1 doubling dilution regardless of the vancomycin susceptibility profile. Eravacycline exhibited MIC90 results of ≤0.06 μg/ml when tested against Streptococcus pneumoniae and beta-hemolytic and viridans group streptococcal isolates. In this surveillance study, eravacycline demonstrated potent in vitro activity against frequently isolated clinical isolates of Gram-positive bacteria (Enterococcus, Staphylococcus, and Streptococcus spp.), including isolates collected over a 5-year period (2013 to 2017), underscoring its potential benefit in the treatment of infections caused by common Gram-positive pathogens.

scholarly journals Activity of Tedizolid against Gram-Positive Clinical Isolates Causing Nosocomial- and Community-Acquired Infections in United States Hospitals (2014–2016)

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S371-S371
Author(s):  
Rodrigo E Mendes ◽  
Dee Shortridge ◽  
S J Ryan Arends ◽  
Helio S Sader ◽  
Mariana Castanheira ◽  
...  
Keyword(s):  
Infection Type ◽  
Bacterial Species ◽  
In Vitro Activity ◽  
Gram Positive ◽  
The Us ◽  
Star Program ◽  
Different Origins ◽  
Hospital Acquired ◽  
Research Grant

Abstract Background Tedizolid (TZD) was approved for the treatment of acute bacterial skin and skin structure infections and is also under investigation for the treatment of hospital-acquired (HA) bacterial pneumonia. The activity of TZD and comparators were evaluated against gram-positive (GP) pathogens causing community (CA)-acquired and HA infections in the US. Methods During the Surveillance of Tedizolid Activity and Resistance (STAR) Program, 10,091 GP isolates were recovered from patients in 31 US hospitals. Isolates were identified by standard biochemical algorithms and MALDI-TOF MS. Susceptibility (S) testing followed CLSI methods and CLSI/EUCAST interpretation. CA and HA infections were defined based on CDC criteria. Results TZD (MIC50/90, 0.12/0.12 µg/mL; 100.0%S) showed equivalent MIC50 and MIC90 values against MSSA and MRSA, regardless of infection type or origin of isolate (Table). Linezolid (LZD; MIC50/90, 0.5–1/1 µg/mL; 100.0%S), daptomycin (DAP; MIC50/90, 0.25/0.5 µg/mL; 99.5–100.0%S), vancomycin (VAN; MIC50/90, 0.5–1/1 µg/mL; 100.0%S) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/≤0.5 µg/mL; 93.0–99.5%S) were also active throughout against MSSA and MRSA, while MICs for other agents varied. TZD (MIC50/90, 0.12/0.25 µg/mL; 100.0%S) activities were consistent against E. faecalis causing various infections from different origins, as were LZD (MIC50/90, 1/1 µg/mL; 100.0%S), ampicillin (MIC50/90, 1/1–2 µg/mL; 100.0%S), DAP (MIC50/90, 1/1–2 µg/mL; 100.0%S), and VAN (MIC50/90, 1/2 µg/mL; 94.9–97.0%S), although these agents had MIC50 and MIC90 values 4- to 8-fold higher than TZD. TZD (MIC50/90, 0.12/0.25 µg/mL), LZD (MIC50/90, 1/1–2 µg/mL; 97.6–100.0%S) and DAP (MIC50/90, 1/2–4 µg/mL; 97.4–100.0%S) were active in vitro against E. faecium, regardless of infection type. S. pneumoniae isolates were S to several drugs tested, and ceftaroline showed the lowest MICs (MIC50/90, ≤0.015/0.06 µg/mL; 100.0%S). Conclusion TZD had potent in vitro activity against GP isolates causing CA and HA infections in US hospitals, regardless of infection site or bacterial species. The TZD in vitro potency was also generally higher than clinically available comparator agents. Disclosures R. E. Mendes, Merck: Research Contractor, Research grant; &#x2028;D. Shortridge, Merck: Research Contractor, Research grant; S. J. R. Arends, Merck: Research Contractor, Research grant; H. S. Sader, Merck: Research Contractor, Research grant; M. Castanheira, Merck: Research Contractor, Research grant; &#x2028;R. K. Flamm, Merck: Research Contractor, Research grant

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