Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy

Chemotherapy ◽  
2019 ◽  
Vol 64 (1) ◽  
pp. 22-27 ◽  
Author(s):  
S. Imindu Liyanage ◽  
Mayuri Gupta ◽  
Fan Wu ◽  
Marcy Taylor ◽  
Michael D. Carter ◽  
...  
Keyword(s):  
Clinical Laboratory ◽  
Optimal Growth ◽  
Microbial Pathogens ◽  
Microdilution Method ◽  
Inhibition Of Growth ◽  
Pantothenate Synthetase ◽  
Broth Microdilution Method ◽  
Competitive Inhibitors ◽  
Derivatives Of ◽  
Enzyme Selectivity

Background: Pantothenate, the fundamental precursor to coenzyme A, is required for optimal growth and virulence of microbial pathogens. It is synthesized by the enzyme-catalyzed condensation of β-alanine and pantoate, which has shown susceptibility to inhibition by analogs of its molecular constituents. Accordingly, analogs of β-alanine are gaining inquiry as potential antimicrobial chemotherapeutics. Methods: We synthesized and evaluated 35 derivatives of β-alanine, substituted at the α, β, amine, and carboxyl sites, derived from in silico, dynamic molecular modeling to be potential competitive inhibitors of pantothenate synthetase. Employing the Clinical Laboratory Standards M7-A6 broth microdilution method, we tested these for inhibition of growth in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Results: All compounds proved entirely ineffective in all species tested, with no inhibition of growth being observed up to 200 µM/mL. Conclusions: Upon revision of the literature, we conclude that high enzyme selectivity or external salvage mechanisms may render this strategy futile against most bacteria.

scholarly journals In Vitro Activities of the New Antifungal Triazole SCH 56592 against Common and Emerging Yeast Pathogens

2000 ◽  
Vol 44 (1) ◽  
pp. 226-229 ◽  
Author(s):  
Francesco Barchiesi ◽  
Daniela Arzeni ◽  
Annette W. Fothergill ◽  
Luigi Falconi Di Francesco ◽  
Francesca Caselli ◽  
...  
Keyword(s):  
Clinical Laboratory ◽  
Clinical Development ◽  
National Committee ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Vitro Data ◽  
In Vitro Data

ABSTRACT A broth microdilution method performed in accordance with the National Committee for Clinical Laboratory Standards guidelines was used to compare the in vitro activity of the new antifungal triazole SCH 56592 (SCH) to that of fluconazole (FLC), itraconazole (ITC), and ketoconazole (KETO) against 257 clinical yeast isolates. They included 220 isolates belonging to 12 different species of Candida, 15 isolates each of Cryptococcus neoformans andSaccharomyces cerevisiae, and seven isolates ofRhodotorula rubra. The MICs of SCH at which 50% (MIC50) and 90% (MIC90) of the isolates were inhibited were 0.06 and 2.0 μg/ml, respectively. In general, SCH was considerably more active than FLC (MIC50 and MIC90 of 1.0 and 64 μg/ml, respectively) and slightly more active than either ITC (MIC50 and MIC90 of 0.25 and 2.0 μg/ml, respectively) and KETO (MIC50 and MIC90 of 0.125 and 4.0 μg/ml, respectively). Our in vitro data suggest that SCH has significant potential for clinical development.

scholarly journals 528. Longitudinal Evaluation of Chlorhexidine Resistance Among Multidrug-Resistant Organisms in Relation to Intervention of Daily Chlorhexidine Bathing in Adult Intensive Care Units

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S254-S254
Author(s):  
Min Ja Kim ◽  
You Seung Chung ◽  
Hojin Lee ◽  
Jin Woong Suh ◽  
Yoojung Cheong ◽  
...  
Keyword(s):  
Intensive Care ◽  
Intensive Care Units ◽  
Clinical Laboratory ◽  
Multidrug Resistant ◽  
University Hospital ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Multidrug Resistant Organisms ◽  
Before And After ◽  
The Republic

Abstract Background Chlorhexidine digluconate (CHG), the most widely used antiseptic, has recently been applied to patient washing to decolonize the multidrug-resistant organisms (MDROs), but there are little data on susceptibilities of MDROs to CHG. The purpose of this study was to evaluate CHG resistance among MDROs before and after the intervention of daily CHG bathing in adult intensive care units (ICUs). Methods The intervention of daily body washing with 2% CHG cloths were taken in adult patients the medical or surgical ICU of 23-bed by a crossover manner for 6 months (MICU, July to December 2017; SICU, January to June 2018) in a 1,050-bed, university hospital in the Republic of Korea. Available MDRO isolates were randomly selected from clinical cultures of ICU patients within 6 months before, during and after the intervention, including MRSA, MR-CoNS, VRE, Carbapenem-resistant Pseudomonas aeruginosa (CR-PA), CR-Acinetobacter baumannii (CR-AB). Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method set by the Clinical Laboratory Standards Institute. Determination of the minimum bactericidal concentrations (MBCs) was performed by subculturing 10 µL from each well without visible microbial growth. Cumulative amounts of CHG used in both ICUs was estimated across the study period from January 2008 to June 2018. Results The cumulative CHG consumption from both ICUs increased sharply from 27,503 g to 29,556 g after one-year intervention. The ranges of MICs and MBCs of CHG among MDRO clinical isolates selected by a 6-month phase are summarized in Table 1. Particularly, CR-PA and CR-AB isolates revealed four to eight times higher MICs and MBCs compared with the majority of Gram-positives excepting some VRE isolates. On the other hand, neither MICs and MBCs ranges of CHG from the MDRO isolates nor the monthly incidence of the MDROs from both ICUs were significantly increased before and after the intervention of daily CHG bathing. Conclusion This study indicates that some Gram-negative MDRO isolates with higher MICs and MBCs of CHG might be from longstanding exposure to CHG or efflux pumps. Although 2% daily CHG bathing uses over 1,000 times higher concentrations than the lethal concentration, it might be needed to monitor CHG resistance among MDROs. Disclosures All authors: No reported disclosures.

scholarly journals Effect of Metronidazole on the Growth of Vaginal Lactobacilliin vitro

2001 ◽  
Vol 9 (1) ◽  
pp. 41-45 ◽  
Author(s):  
Jose A. Simoes ◽  
Alla A. Aroutcheva ◽  
Susan Shott ◽  
Sebastian Faro
Keyword(s):  
Adverse Effect ◽  
Hydrogen Peroxide ◽  
Antimicrobial Agent ◽  
Clinical Laboratory ◽  
National Committee ◽  
Broth Microdilution ◽  
High Concentration ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
The Ideal

Objective:To determine whether metronidazole has an adverse effect on the growth ofLactobacillus.Methods:Hydrogen peroxide- and bacteriocin-producing strains ofLactobacilluswere used as test strains. Concentrations of metronidazole used ranged from 128 to 7000 μg/ml. Susceptibility to metronidazole was conducted by the broth microdilution method recommended by the National Committee for Clinical Laboratory Standards.Results:Growth ofLactobacilluswas partially inhibited at concentrations between 1000 and 4000 μg/ml (p= 0.014). Concentrations ≥ 5000 μg/ml completely inhibited growth ofLactobacillus. Concentrations between 128 and 256 μg/ml stimulated growth ofLactobacillus(p= 0.025 and 0.005, respectively). Concentrations of metronidazole between 64 and 128 μg/ml or ≥ 512 μg/ml did not have an inhibitory or a stimulatory effect on the growth ofLactobacilluscompared to the control.Conclusions:High concentration of metronidazole, i.e. between 1000 and 4000 μg/ml, partially inhibited the growth ofLactobacillus. Concentrations ≥ 5000 μg/ml completely suppressed the growth ofLactobacillus. Concentrations between ≥ 128 and ≤ 256 μg/ml stimulated the growth ofLactobacillus. Further investigation to determine the ideal concentration of metronidazole is needed in order to use the antimicrobial agent effectively in the treatment of bacterial vaginosis.

scholarly journals Evaluation of a Scanner-Assisted Colorimetric MIC Method for Susceptibility Testing of Gram-Negative Fermentative Bacteria

2004 ◽  
Vol 70 (4) ◽  
pp. 2398-2403 ◽  
Author(s):  
Mokhlasur Rahman ◽  
Inger Kühn ◽  
Motiur Rahman ◽  
Barbro Olsson-Liljequist ◽  
Roland Möllby
Keyword(s):  
Bacterial Growth ◽  
Susceptibility Testing ◽  
Clinical Laboratory ◽  
National Committee ◽  
Broth Microdilution ◽  
Gram Negative ◽  
Microdilution Method ◽  
Epidemiological Surveys ◽  
Fermentative Bacteria ◽  
Broth Microdilution Method

ABSTRACT We describe the ScanMIC method, a colorimetric MIC method for susceptibility testing of gram-negative fermentative bacteria. The method is a slight modification of the National Committee for Clinical Laboratory Standards (NCCLS) recommended broth microdilution method that uses a redox indicator 2,3,5-triphenyltetrazolium chloride (TTC) to enhance the estimate of bacterial growth inhibition in a microplate and a flatbed scanner to capture the microplate image. In-house software was developed to transform the microplate image into numerical values based on the amount of bacterial growth and to generate the MICs automatically. The choice of indicator was based on its low toxicity and ease of reading by scanner. We compared the ScanMIC method to the NCCLS recommended broth microdilution method with 197 coliform strains against seven antibacterial agents. The interpretative categorical agreement was obtained in 92.4% of the assays, and the agreement for MIC differences (within ±1 log2 dilution) was obtained in 96% for ScanMIC versus broth microdilution and 97% for a two-step incubation colorimetric broth microdilution versus the broth microdilution method. The method was found to be labor-saving, not to require any initial investment, and to show reliable results. Thus, the ScanMIC method could be useful for epidemiological surveys that include susceptibility testing of bacteria.

scholarly journals Evaluation of Disk Diffusion Method for Determining Posaconazole Susceptibility of Filamentous Fungi: Comparison with CLSI Broth Microdilution Method

2006 ◽  
Vol 50 (3) ◽  
pp. 1108-1111 ◽  
Author(s):  
E. López-Oviedo ◽  
A. I. Aller ◽  
C. Martín ◽  
C. Castro ◽  
M. Ramirez ◽  
...  
Keyword(s):  
Filamentous Fungi ◽  
Clinical Laboratory ◽  
Culture Media ◽  
Disk Diffusion ◽  
Diffusion Method ◽  
Broth Microdilution ◽  
Disk Diffusion Method ◽  
Microdilution Method ◽  
Broth Microdilution Method

ABSTRACT The disk diffusion method was evaluated for determining posaconazole susceptibility against 78 strains of molds using two culture media in comparison with the CLSI (Clinical Laboratory Standards Institute) broth microdilution method (M38-A). A significant correlation between disk diffusion and microdilution methods was observed with both culture media.

scholarly journals In Vitro Activity of A-192411.29, a Novel Antifungal Lipopeptide

2000 ◽  
Vol 44 (5) ◽  
pp. 1242-1246 ◽  
Author(s):  
Angela M. Nilius ◽  
Patti M. Raney ◽  
Dena M. Hensey-Rudloff ◽  
Weibo Wang ◽  
Qun Li ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Clinical Laboratory ◽  
Vitro Activity ◽  
National Committee ◽  
In Vitro Activity ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Structural Template ◽  
Better Than

ABSTRACT A-192411.29 is a novel antifungal agent derived from the structural template of the natural product echinocandin. The in vitro activity of A-192411.29 against common pathogenic yeasts was assessed by National Committee for Clinical Laboratory Standards method M27-A. It demonstrated broad-spectrum, fungicidal activity and was active against the most clinically relevant yeasts, such as Candida albicans, Candida tropicalis, and Candida glabrata, as well as less commonly encounteredCandida species; in general, its potency on a weight basis was comparable to that of amphotericin B. It maintained potent in vitro activity against Candida strains with reduced susceptibilities to fluconazole and amphotericin B. The in vitro activity of A-192411.29 against Cryptococcus neoformans was comparable to its activity against Candida spp. However, A-192411.29 did not demonstrate complete growth inhibition ofAspergillus fumigatus by the broth microdilution method used. A-192411.29 possesses an antifungal profile comparable to or better than those of fluconazole and amphotericin B against pathogenic yeasts, including strains resistant to fluconazole or amphotericin B, suggesting that it may be a therapeutically useful new antifungal drug.

scholarly journals In Vitro Activities of a New Lipopeptide Antifungal Agent, FK463, against a Variety of Clinically Important Fungi

2000 ◽  
Vol 44 (1) ◽  
pp. 57-62 ◽  
Author(s):  
Shuichi Tawara ◽  
Fumiaki Ikeda ◽  
Katsuyuki Maki ◽  
Yoshihiko Morishita ◽  
Kazumi Otomo ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Clinical Laboratory ◽  
Inoculum Size ◽  
Cross Resistance ◽  
National Committee ◽  
Minimum Fungicidal Concentration ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Spectrum Activity

ABSTRACT The in vitro antifungal activity and spectrum of FK463 were compared with those of amphotericin B, fluconazole, and itraconazole by using a broth microdilution method specified by National Committee for Clinical Laboratory Standards document M27-A (National Committee for Clinical Laboratory Standards, Wayne, Pa., 1997). FK463 exhibited broad-spectrum activity against clinically important pathogens including Candida species (MIC range, ≦0.0039 to 2 μg/ml) and Aspergillus species (MIC range, ≦0.0039 to 0.0313 μg/ml), and its MICs for such fungi were lower than those of the other antifungal agents tested. FK463 was also potently active against azole-resistant Candida albicans as well as azole-susceptible strains, and there was no cross-resistance with azoles. FK463 showed fungicidal activity against C. albicans, i.e., a 99% reduction in viability after a 24-h exposure at concentrations above 0.0156 μg/ml. The minimum fungicidal concentration (MFC) assays indicated that FK463 was fungicidal against most isolates of Candida species. In contrast, the MFCs of FK463 for A. fumigatus isolates were much higher than the MICs, indicating that its action is fungistatic against this species. FK463 had no activity against Cryptococcus neoformans,Trichosporon species, or Fusarium solani. Neither the test medium (kind and pH) nor the inoculum size greatly affected the MICs of FK463, while the addition of 4% human serum albumin increased the MICs for Candida species and A. fumigatus more than 32 times. Results from preclinical in vitro evaluations performed thus far indicate that FK463 should be a potent parenteral antifungal agent.

scholarly journals Synthesis and anti–microbial activity of 1,2,3–triazole tethered nitroguiacol ethers

2019 ◽  
pp. 329-334 ◽  
Author(s):  
Sridhar Rachakonda ◽  
Fatima Naaz ◽  
Intzar Ali ◽  
Prasad K. R. S. ◽  
V. Basaveswara Rao Mandava ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activities ◽  
Microbial Pathogens ◽  
Marine Microorganisms ◽  
Broth Microdilution ◽  
Microbial Activities ◽  
Microdilution Method ◽  
Wide Range ◽  
Broth Microdilution Method ◽  
Spectrum Activity

Nitro aromatic/nitrophenols have been widely distributed in nature and are mostly isolated from marine microorganisms and had shown a broad spectrum of anti–microbial activities against a wide range of microbial pathogens. The objective of the present work is to Synthesize some new 1,2,3–triazole tethered nitroguiacol ethers and evaluated of their anti–bacterial and anti–fungal activities. A focused library of 1,2,3-triazole tethered nitroguiacol ethers were prepared by employing Cu (I) catalyzed click chemistry reaction and evaluated for their antimicrobial activities by broth microdilution method. Among the tested compounds, compounds 8e, 8f, 8g, and 8i exhibited broad–spectrum activity against selected pathogenic strains, with the MIC of 8 µg/mL for gram–positive bacteria (Staphylococcus aureus), 16 µg/mL for Pseudomonas aeruginosa (gram–negative bacteria), and Candida species, respectively. Future investigations with this class of compounds may lead to the development of potential candidates for antimicrobial drug discovery. 

scholarly journals Isolation, identification and antifungal susceptibility of Candida in patients with fungal sepsis

2019 ◽  
Vol 7 (7) ◽  
pp. 2542
Author(s):  
Bilal Ahmad Wani ◽  
Mohd Rafiq Lone ◽  
Najmus Saqib
Keyword(s):  
Candida Albicans ◽  
Candida Species ◽  
Clinical Laboratory ◽  
Antifungal Susceptibility ◽  
Tertiary Care ◽  
Resistance Pattern ◽  
National Committee ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Susceptibility Tests

Background: In this study, our aim was to identify and isolate Candida species from patients admitted in ICU,s of our hospital and to determine their susceptibilities to various antifungal agents so as to find the local resistance pattern and guide for empirical treatment.Methods: In our study 37 strains of candida were isolated (4 Candida albicans, 33 Non-albicans Candida strains). Candida species were identified by conventional, biochemical and molecular methods. Antifungal susceptibility tests for amphotericin B, fluconazole, itraconazole, ketoconazole and voriconazole were performed with broth microdilution method and E- tests as described by National Committee for Clinical Laboratory Standards (NCCLS).Results: Out of 37 Candida strains, the most prevalent species were C. tropicalis (43.2%), C. parapsilosis (24.3%), C. krusei (16.2%), C. albicans (10.8%), and C. glabrata (2.7%). Among all strains four strains (10.8 %) were resistant, two Candida albicans where found resistant to fluconazole one Candida krusei and one Candida parapsilosis were found to be resistant to all azoles.Conclusions: Candidemia continues to be associated with substantial morbidity and mortality and non albicans Candida species are the commonly isolated pathogen from those patients admitted in tertiary care hospitals in Indian scenario. Thus, it is imperative to perform antifungal susceptibility to select appropriate and effective antifungal therapy.

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