scholarly journals Synergistic Antimicrobial Activities of Folic Acid Antagonists and Nucleoside Analogs

2009 ◽  
Vol 54 (3) ◽  
pp. 1226-1231 ◽  
Author(s):  
Johannes Zander ◽  
Silke Besier ◽  
Hanns Ackermann ◽  
Thomas A. Wichelhaus
Keyword(s):  
Folic Acid ◽  
Nucleoside Analogs ◽  
Bactericidal Effect ◽  
Antimicrobial Activities ◽  
Nucleoside Analog ◽  
Folic Acid Antagonists ◽  
Bacterial Utilization ◽  
Time Kill ◽  
Derivatives Of

ABSTRACT The antimicrobial activities of folic acid antagonists are supposed to be antagonized by elevated extracellular thymidine concentrations in damaged host tissues. Therefore, this study was aimed at screening for nucleoside analogs that impair bacterial thymidine utilization and analyzing the combined antimicrobial activities of nucleoside analogs and folic acid antagonists in the presence of thymidine. Our screening results revealed that different nucleoside analogs, in particular halogenated derivatives of 2′-deoxyuridine, substantially impaired the bacterial utilization of extracellular thymidine in Staphylococcus aureus. Time-kill methods showed that 5-iodo-2′-deoxyuridine enhanced the extent of killing of trimethoprim-sulfamethoxazole (SXT) at 24 h against S. aureus in the presence of thymidine (200 μg/liter). While SXT (40 mg/liter) alone did not kill bacteria in the presence of thymidine, its combination with the nucleoside analog at a concentration of 8 μmol/liter showed a bactericidal effect. Moreover, 5-iodo-2′-deoxyuridine combined with SXT in the presence of thymidine showed a broad spectrum of activity against several Gram-positive and Gram-negative bacteria. In conclusion, these data provide evidence that the in vitro antimicrobial activity of SXT in the presence of thymidine can be significantly improved by combination with a nucleoside analog.

scholarly journals Antimicrobial Properties of 8-Hydroxyserrulat-14-en-19-oic Acid for Treatment of Implant-Associated Infections

2012 ◽  
Vol 57 (1) ◽  
pp. 333-342 ◽  
Author(s):  
Justyna Nowakowska ◽  
Hans J. Griesser ◽  
Marcus Textor ◽  
Regine Landmann ◽  
Nina Khanna
Keyword(s):  
Structural Changes ◽  
Treatment Options ◽  
Antimicrobial Properties ◽  
Bactericidal Effect ◽  
Mouse Tissue ◽  
Logarithmic Phase ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Time Kill

ABSTRACTTreatment options are limited for implant-associated infections (IAI) that are mainly caused by biofilm-forming staphylococci. We report here on the activity of the serrulatane compound 8-hydroxyserrulat-14-en-19-oic acid (EN4), a diterpene isolated from the Australian plantEremophila neglecta. EN4 elicited antimicrobial activity toward various Gram-positive bacteria but not to Gram-negative bacteria. It showed a similar bactericidal effect against logarithmic-phase, stationary-phase, and adherentStaphylococcus epidermidis, as well as against methicillin-susceptible and methicillin-resistantS. aureuswith MICs of 25 to 50 μg/ml and MBCs of 50 to 100 μg/ml. The bactericidal activity of EN4 was similar againstS. epidermidisand its Δicamutant, which is unable to produce polysaccharide intercellular adhesin-mediated biofilm. In time-kill studies, EN4 exhibited a rapid and concentration-dependent killing of staphylococci, reducing bacterial counts by >3 log10CFU/ml within 5 min at concentrations of >50 μg/ml. Investigation of the mode of action of EN4 revealed membranolytic properties and a general inhibition of macromolecular biosynthesis, suggesting a multitarget activity.In vitro-tested cytotoxicity on eukaryotic cells was time and concentration dependent in the range of the MBCs. EN4 was then tested in a mouse tissue cage model, where it showed neither bactericidal nor cytotoxic effects, indicating an inhibition of its activity. Inhibition assays revealed that this was caused by interactions with albumin. Overall, these findings suggest that, upon structural changes, EN4 might be a promising pharmacophore for the development of new antimicrobials to treat IAI.

scholarly journals Microbial Transformations of Isophorone by Alternaria alternata and Neurospora crassa

2013 ◽  
Vol 8 (1) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Ismail Kiran ◽  
Özge Özşen ◽  
Turgay Çelik ◽  
Semra İlhan ◽  
Bükay Yenice Gürsu ◽  
...  
Keyword(s):  
Neurospora Crassa ◽  
Alternaria Alternata ◽  
Antimicrobial Agents ◽  
Antimicrobial Activities ◽  
Anti Oxidant ◽  
Agar Dilution ◽  
Important Field ◽  
Pharmacology And Toxicology ◽  
Derivatives Of

Isophorone (3,5,5-trimethyl-2-cyclohexen-1-one), a monoterpene, and the structurally related 1,8-cineole and camphor, have demonstrated a protective effect against cancer, biological activity against a variety of microorganisms, and anti-oxidant properties. The derivatization of isophorone is, therefore, an important field of xenobiochemistry, pharmacology and toxicology. The aim of this study was to obtain derivatives of isophorone through microbial biotransformation and evaluate the biotransformation metabolites as potential antimicrobial agents. Incubation of isophorone with the fungi Alternaria alternata and Neurospora crassa afforded 4α-hydroxy- and 7-hydroxy-isophorone as transformation metabolites. The antimicrobial activities of isophorone and the metabolites were evaluated in vitro both by using agar dilution and microdilution methods. However, no significant antibacterial activity was observed when compared with those of standard substances.

scholarly journals Human Immunodeficiency Virus Types 1 and 2 Exhibit Comparable Sensitivities to Zidovudine and Other Nucleoside Analog Inhibitors In Vitro

2007 ◽  
Vol 52 (1) ◽  
pp. 329-332 ◽  
Author(s):  
Robert A. Smith ◽  
Geoffrey S. Gottlieb ◽  
Donovan J. Anderson ◽  
Crystal L. Pyrak ◽  
Bradley D. Preston
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Reverse Transcriptase ◽  
Antiviral Therapy ◽  
Nucleoside Analogs ◽  
Nucleoside Analog ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Indicator Cell

ABSTRACT Using an indicator cell assay that directly quantifies viral replication, we show that human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2, respectively) exhibit similar sensitivities to 3′-azido-3′-deoxythymidine (zidovudine) as well as other nucleoside analog inhibitors of reverse transcriptase. These data support the use of nucleoside analogs for antiviral therapy of HIV-2 infection.

scholarly journals In Vitro Anti-Helicobacter pyloriActivities of New Rifamycin Derivatives, KRM-1648 and KRM-1657

1999 ◽  
Vol 43 (5) ◽  
pp. 1072-1076 ◽  
Author(s):  
Junko K. Akada ◽  
Mutsunori Shirai ◽  
Kenji Fujii ◽  
Kiwamu Okita ◽  
Teruko Nakazawa
Keyword(s):  
Helicobacter Pylori ◽  
Cell Lysis ◽  
Antimicrobial Activities ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bactericidal Activities ◽  
H Pylori ◽  
Time Kill

ABSTRACT The new rifamycin derivatives KRM-1657 and KRM-1648 were evaluated for their in vitro antimicrobial activities against 44 strains ofHelicobacter pylori. Although the drugs were not very active against other gram-negative bacteria, the MICs at which 90% of isolates are inhibited for these drugs were lower (0.002 and 0.008 μg/ml, respectively) than those of amoxicillin and rifampin forH. pylori. Time-kill studies revealed that the bactericidal activities of these agents were due to cell lysis. The results presented here indicate that these new rifamycin derivatives may be useful for the eradication of H. pylori infections.

scholarly journals In Vitro Activities of Membrane-Active Peptides Alone and in Combination with Clinically Used Antimicrobial Agents against Stenotrophomonas maltophilia

2000 ◽  
Vol 44 (6) ◽  
pp. 1716-1719 ◽  
Author(s):  
A. Giacometti ◽  
O. Cirioni ◽  
M. S. Del Prete ◽  
F. Barchiesi ◽  
M. Fortuna ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Antimicrobial Agents ◽  
Antimicrobial Activities ◽  
Active Peptides ◽  
Cecropin P1 ◽  
Polymyxin E ◽  
Membrane Active Peptides ◽  
Magainin Ii ◽  
Time Kill

ABSTRACT The in vitro activities of buforin II, cecropin P1, and magainin II, alone and in combination with six clinically used antimicrobial agents, against 12 clinical isolates of Stenotrophomonas maltophilia were investigated. Antimicrobial activities were measured by MIC and time-kill studies. The isolates were susceptible to the peptides at concentrations in the range of 0.50 to 16 μg/ml. Synergy was observed when the peptides were combined with polymyxin E, meropenem, ceftazidime, piperacillin, and clarithromycin.

scholarly journals Microwave Induced Synthesis and Antimicrobial Activities of Some Derivatives of 3, 5-Diaryl-2-pyrazoline-1-carbaldehyde

2010 ◽  
Vol 7 (2) ◽  
pp. 496-500 ◽  
Author(s):  
Ravindra Kumar ◽  
Y. K. Srivastava
Keyword(s):  
Antibacterial Activity ◽  
Hydrazine Hydrate ◽  
Antimicrobial Activities ◽  
Derivatives Of ◽  
Phenylene Diamine

3, 5-Diaryl-2-pyrazoline-1-carbaldehyde(1)was condensed with hydrazine hydrate ando-phenylene diamine to afford corresponding hydrazones(2)and 3-benzimidazolyl-3, 5-diaryl-2-pyrazoline respectively under MWI condition. The newly synthesized compounds have been screened for their antibacterial activityin vitro.

scholarly journals In Vitro Antimicrobial Activities of Novel Anilinouracils Which Selectively Inhibit DNA Polymerase III of Gram-Positive Bacteria

2000 ◽  
Vol 44 (8) ◽  
pp. 2217-2221 ◽  
Author(s):  
Jennifer S. Daly ◽  
Theodore J. Giehl ◽  
Neal C. Brown ◽  
Chengxin Zhi ◽  
George E. Wright ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Antimicrobial Activities ◽  
Dna Polymerase Iii ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
New Agents ◽  
Gram Positive Bacteria ◽  
Polymerase Iii ◽  
Time Kill

ABSTRACT The 6-anilinouracils are novel dGTP analogs that selectively inhibit the replication-specific DNA polymerase III of gram-positive eubacteria. Two specific derivatives, IMAU (6-[3′-iodo-4′-methylanilino]uracil) and EMAU (6-[3′-ethyl-4′-methylanilino]uracil), were substituted with either a hydroxybutyl (HB) or a methoxybutyl (MB) group at their N3 positions to produce four agents: HB-EMAU, MB-EMAU, HB-IMAU, and MB-IMAU. These four new agents inhibited Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Time-kill assays and broth dilution testing confirmed bactericidal activity. These anilinouracil derivatives represent a novel class of antimicrobials with promising activities against gram-positive bacteria that are resistant to currently available agents, validating replication-specific DNA polymerase III as a new target for antimicrobial development.

scholarly journals In Vitro Activities of Garenoxacin (BMS-284756) against Streptococcus pneumoniae, Viridans Group Streptococci, and Enterococcus faecalis Compared to Those of Six Other Quinolones

2003 ◽  
Vol 47 (11) ◽  
pp. 3542-3547 ◽  
Author(s):  
Patrick Grohs ◽  
Serge Houssaye ◽  
Agnès Aubert ◽  
Laurent Gutmann ◽  
Emmanuelle Varon
Keyword(s):  
Streptococcus Pneumoniae ◽  
Enterococcus Faecalis ◽  
Bactericidal Effect ◽  
Clinical Isolates ◽  
Active Efflux ◽  
Resistant Strains ◽  
Different Strains ◽  
Viridans Group Streptococci ◽  
Derivatives Of

ABSTRACT The activity of garenoxacin, a new quinolone, was determined in comparison with other quinolones against different strains of S. pneumoniae, viridans group streptococci (VGS), and Enterococcus faecalis. Strains were quinolone-susceptible clinical isolates and quinolone-resistant strains with defined mechanisms of resistance obtained from either clinical isolates or derivatives of S. pneumoniae R6. Clinical quinolone-susceptible strains of S. pneumoniae, VGS and E. faecalis showed garenoxacin MICs within a range of 0.03 μg/ml to 0.25 μg/ml. Garenoxacin MICs increased two- to eightfold when one mutation was present in the ParC quinolone resistance-determining region (QRDR), fourfold when one mutation was present in the GyrA QRDR (S. pneumoniae), 8- to 64-fold when two or three mutations were associated in ParC and GyrA QRDR, and 2,048-fold when two mutations were present in both the GyrA and ParC QRDRs (Streptococcus pneumoniae). Increased active efflux had a moderate effect on garenoxacin MICs for S. pneumoniae and VGS. Against S. pneumoniae, garenoxacin behaved like moxifloxacin and sparfloxacin, being more affected by a single gyrA mutation than by a single parC mutation. Although garenoxacin was generally two- to fourfold more active than moxifloxacin against the different wild-type or mutant strains of S. pneumoniae, VGS, and E. faecalis, it was two- to fourfold less active than gemifloxacin. At four times the respective MIC for each strain, the bactericidal effect of garenoxacin, observed at 6 h for S. pneumoniae and at 24 h for S. oralis and E. faecalis, was not influenced by the presence of mutation either in the ParC or in both the ParC and GyrA QRDRs.

scholarly journals WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent “β-Lactam Enhancer” Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Bartolome Moya ◽  
Isabel M. Barcelo ◽  
Sachin Bhagwat ◽  
Mahesh Patel ◽  
German Bou ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Risk ◽  
Bactericidal Activity ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Enhancer Activity ◽  
Content Type ◽  
Steady State Kinetics ◽  
Time Kill ◽  
Derivatives Of

ABSTRACT Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against Pseudomonas aeruginosa, including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (mexR), porin-deficient (oprD), and AmpC-hyperproducing (dacB) derivatives of PAO1, and MBL-expressing clinical strains ST175 (bla VIM-2) and ST111 (bla VIM-1). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent Ki [Ki app] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the P. aeruginosa mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam–WCK enhancer combinations represent a promising β-lactam “enhancer-based” approach to treat MDR P. aeruginosa infections, bypassing the need for MBL inhibition.

scholarly journals Time-kill curve analysis and pharmacodynamic functions for in vitro evaluation of antimicrobials againstNeisseria gonorrhoeae

2015 ◽  
Author(s):  
Sunniva Foerster ◽  
Magnus Unemo ◽  
Lucy J Hathaway ◽  
Nicola Low ◽  
Christian L Althaus
Keyword(s):  
Bactericidal Effect ◽  
World Health ◽  
Transmitted Infection ◽  
In Vitro Evaluation ◽  
Sexually Transmitted ◽  
Dosing Strategies ◽  
Kill Curve ◽  
Health Organization ◽  
Time Kill

Gonorrhea is a sexually transmitted infection caused by the Gram-negative bacteriumNeisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to appropriately evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic functions, which describe the relationship between the concentration of antimicrobials and the bacterial net growth rate, provide more detailed information than the MIC only. In this study, a novel standardized in vitro time-kill curve assay was developed. The assay was validated using five World Health OrganizationN. gonorrhoeaereference strains and various concentrations of ciprofloxacin, and then the activity of nine antimicrobials with different target mechanisms were examined against a highly susceptible clinical wild type isolate (cultured in 1964). From the time-kill curves, the bacterial net growth rates at each antimicrobial concentration were estimated. Finally, a pharmacodynamic function was fitted to the data, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. Ciprofloxacin resistance determinants shifted the pharmacodynamic MIC (zMIC) and attenuated the bactericidal effect at antimicrobial concentrations above the zMIC. Ciprofloxacin, spectinomycin and gentamicin had the strongest bactericidal effect during the first six hours of the assay. Only tetracycline and chloramphenicol showed a purely bacteriostatic effect. The pharmacodynamic functions differed between antimicrobials, showing that the effect of the drugs at concentrations below and above the MIC vary widely. In conclusion,N. gonorrhoeaetime-kill curve experiments analyzed with pharmacodynamic functions have potential for in vitro evaluation of new and existing antimicrobials and dosing strategies to treat gonorrhea.

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