scholarly journals Activity of and Development of Resistance to Corallopyronin A, an Inhibitor of RNA Polymerase

2011 ◽  
Vol 55 (5) ◽  
pp. 2413-2416 ◽  
Author(s):  
Katherine Mariner ◽  
Martin McPhillie ◽  
Rachel Trowbridge ◽  
Catriona Smith ◽  
Alex J. O'Neill ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Rna Polymerase ◽  
Inhibitory Concentration ◽  
Drug Candidate ◽  
Antibacterial Drug ◽  
Content Type ◽  
Development Of Resistance ◽  
Bacterial Rna ◽  
Resistant Mutants

ABSTRACTWe explored the properties of corallopyronin A (CorA), a poorly characterized inhibitor of bacterial RNA polymerase (RNAP). It displayed a 50% inhibitory concentration of 0.73 μM against RNAP, compared with 11.5 nM for rifampin. The antibacterial activity of CorA was also inferior to rifampin, and resistant mutants ofStaphylococcus aureuswere easily selected. The mutations conferring resistance resided in therpoBandrpoCsubunits of RNAP. We conclude that CorA is not a promising antibacterial drug candidate.

scholarly journals Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase: pseudouridimycin

2017 ◽  
Author(s):  
Sonia I. Maffioli ◽  
Yu Zhang ◽  
David Degen ◽  
Thomas Carzaniga ◽  
Giancarlo Del Gatto ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Drug Development ◽  
Rna Polymerase ◽  
Binding Site ◽  
Bacterial Pathogens ◽  
Nucleoside Analog ◽  
Cross Resistance ◽  
Nucleoside Triphosphate ◽  
Antibacterial Drug ◽  
Bacterial Rna

There is an urgent need for new antibacterial drugs effective against bacterial pathogens resistant to current drugs1–2. Nucleoside-analog inhibitors (NAIs) of viral nucleotide polymerases have had transformative impact in treatment of HIV3and HCV4. NAIs of bacterial RNA polymerase (RNAP) potentially could have major impact on treatment of bacterial infection, particularly because functional constraints on substitution of RNAP nucleoside triphosphate (NTP) binding sites4-5could limit resistance emergence4-5. Here we report the discovery, from microbial extract screening, of an NAI that inhibits bacterial RNAP and exhibits antibacterial activity against a broad spectrum of drug-sensitive and drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a novel microbial natural product consisting of a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, potently and selectively inhibits bacterial growth in culture, and potently clears infection in a mouse model ofStreptococcus pyogenesperitonitis. PUM inhibits RNAP through a binding site on RNAP (the "i+1" NTP binding site) and mechanism (competition with UTP for occupancy of the "i+1" NTP binding site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. The results provide the first example of a selective NAI of bacterial RNAP, provide an advanced lead compound for antibacterial drug development, and provide structural information and synthetic routes that enable lead optimization for antibacterial drug development.

scholarly journals A Novel 6-Benzyl Ether Benzoxaborole Is Active against Mycobacterium tuberculosisIn Vitro

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Nipul Patel ◽  
Theresa O'Malley ◽  
Yong-Kang Zhang ◽  
Yi Xia ◽  
Bjorn Sunde ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Liquid Medium ◽  
Inhibitory Concentration ◽  
Solid Medium ◽  
Eukaryotic Cells ◽  
Intracellular Bacteria ◽  
Benzyl Ether ◽  
Content Type ◽  
Resistant Mutants

ABSTRACT We identified a novel 6-benzyl ether benzoxaborole with potent activity against Mycobacterium tuberculosis. The compound had an MIC of 2 μM in liquid medium. The compound was also able to prevent growth on solid medium at 0.8 μM and was active against intracellular bacteria (50% inhibitory concentration [IC50] = 3.6 μM) without cytotoxicity against eukaryotic cells (IC50 > 100 μM). We isolated resistant mutants (MIC ≥ 100 μM), which had mutations in Rv1683, Rv3068c, and Rv0047c.

scholarly journals Emergence of Linezolid-Resistant Mutants in a Susceptible-Cell Population of Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (5) ◽  
pp. 2466-2468 ◽  
Author(s):  
Yurika Ikeda-Dantsuji ◽  
Hideaki Hanaki ◽  
Taiji Nakae ◽  
Yoshio Takesue ◽  
Kazunori Tomono ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Population ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Rrna Genes ◽  
Chloramphenicol Resistance ◽  
Methicillin Resistant ◽  
Content Type ◽  
Susceptible Cell ◽  
Linezolid Therapy ◽  
Resistant Mutants

ABSTRACTMethicillin-resistantStaphylococcus aureuswith a MIC of linezolid of 4 μg/ml, isolated from a patient who had undergone unsuccessful linezolid therapy, yielded linezolid-resistant mutants in blood agar at 48 h of incubation. The resistant clones showed a MIC of linezolid ranging from 8 to 64 μg/ml and accumulated the T2500A mutation(s) of the rRNA genes. Emergence of these resistant clones appears to be facilitated by a cryptic mutation or mutations associated with chloramphenicol resistance.

scholarly journals Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Debora Rubio-Aparicio ◽  
Thomas G. Nolan ◽  
Jonathan Parkinson ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Hollow Fiber ◽  
Phase 1 ◽  
Phase 3 ◽  
Fiber Model ◽  
Content Type ◽  
Development Of Resistance ◽  
Carbapenem Resistant ◽  
Dosage Regimens

ABSTRACT The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

In-Vitro Studies on the Sensitivity of Staphylococcus aureus to Some Ethno-Medicinal Preparations Sold around Kano, Nigeria

2011 ◽  
Vol 4 (1) ◽  
pp. 22-25 ◽  
Author(s):  
M Bashir ◽  
I Yusuf ◽  
AS Kutama
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Test Organism ◽  
Ethanolic Extract ◽  
Screening Tests ◽  
Phytochemical Screening ◽  
Herbal Preparations

Five traditional herbal preparations were sampled between May-June, 2009 in Kano. The samples were investigated for invitro antibacterial activities against clinical isolates of Staphylococcus aureus. Likewise, phytochemical screening tests were conducted to determine some of the phytochemicals present in the ethanolic and water extracts of the samples. Various concentrations of the extracts were prepared using serial doubling dilutions (5000=l/ml, 2500=g/ml, 1250=g/ml, 625=g/ml and 312.5=g/ml). All the test extracts showed slight antibacterial activity against the test organism, with ethanolic extract of sample E having the highest zone diameter of inhibition, while sample H had the lowest diameter of inhibition. The standard antibiotic disc (Gentamicin) had demonstrated the highest activity on the test organisms. The results of the Phytochemical screening revealed the presence of steroid in all the samples, tannin in samples A, C, D and E, reducing sugars in sample A, D and E respectively. The result of the minimum inhibitory concentration (MIC) was found to be above 312.5=g/ml for samples C, D and E. Keywords: Staphylococcus aureus, Herbal preparations, antibacterial activity, Phytochemical screening and minimum inhibitory concentration.

scholarly journals Synthesis of zinc oxide and silver nanoparticles using ficus palmata - Forssk leaf extracts and assessment of antibacterial activity

2020 ◽  
Vol 26 (6) ◽  
pp. 200454-0
Author(s):  
Sabaoon Shamshad ◽  
Jamshaid Rashid ◽  
Ihsan-ul-haq ◽  
Naseem Iqbal ◽  
Saif Ullah Awan
Keyword(s):  
Staphylococcus Aureus ◽  
Silver Nanoparticles ◽  
Zinc Oxide ◽  
Antibacterial Activity ◽  
Zinc Oxide Nanoparticles ◽  
Inhibitory Concentration ◽  
Oxide Nanoparticles ◽  
Leaf Extracts ◽  
E Coli ◽  
Ficus Palmata

Multidrug resistance of bacteria is an emerging human health hazard and warrants development of novel antibacterial agents with more effective mode of action. Here, zinc oxide and silver nanomaterials were prepared using Ficus palmata Forssk leaf extract with efficient antibacterial activity. SEM coupled with EDS confirmed the spherical symmetry with average particle diameter 50 to 65 nm while the XRD confirmed crystalline face centered cubic structure of silver and hexagonal crystallize phase of zinc oxide nanoparticles. Antibacterial activity was evaluated for 8 pathogenic bacterial strains including 3 drug resistant pathogenic strains. The nanoparticles showed enhanced growth inhibition for resistant strains in comparison with the broad-spectrum antibiotics i.e. roxithromycin and cefixime. Minimum inhibitory concentration in μg.mL<sup>-1</sup> of silver nanoparticles was found to be as low as 33.3 for resistant Streptococcus haemolyticus; 11.1 for Staphylococcus aureus and E Coli; and 3.7 μg.mL<sup>-1</sup> for resistant Pseudomonas aeruginosa. Similarly, the minimum inhibitory concentration of zinc oxide nanoparticles was found to be 100 μg.mL<sup>-1</sup> against resistant Streptococcus haemolyticus and Staphylococcus aureus; 11.1 μg.mL<sup>-1</sup> for resistant Pseudomonas aeruginosa; and 3.7 μg.mL<sup>-1</sup> against resistant E coli. Ficus palmata Forssk leaf extracts can be explored effectively for synthesizing active antibacterial nanomaterials as a non-toxic and environmentally benign synthesis route.

scholarly journals Daptomycin plus Fosfomycin, a Synergistic Combination in Experimental Implant-Associated Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus in Rats

2014 ◽  
Vol 59 (2) ◽  
pp. 859-863 ◽  
Author(s):  
Tilman Lingscheid ◽  
Wolfgang Poeppl ◽  
Dominik Bernitzky ◽  
Luzia Veletzky ◽  
Manuel Kussmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Once Daily ◽  
Methicillin Resistant ◽  
Bacterial Counts ◽  
Content Type ◽  
Bacterial Cultures ◽  
Development Of Resistance ◽  
Bacterial Inoculum ◽  
Titanium Wire ◽  
Mrsa Infection

ABSTRACTThe aim of this study was to evaluate the combination of daptomycin and fosfomycin in experimental chronic implant-associated osteomyelitis due to methicillin-resistantStaphylococcus aureus(MRSA). Infection was induced in the tibiae of rats by the insertion of a bacterial inoculum (1 to 5 × 108CFU/ml) of a clinical MRSA isolate and a titanium wire. Four weeks after infection, each animal was assigned to a treatment group: daptomycin monotherapy at 60 mg/kg of body weight once daily (n= 10), fosfomycin monotherapy at 40 mg/kg once daily (n= 10), or daptomycin and fosfomycin combined at 60 mg/kg and 40 mg/kg, respectively, once daily (n= 9). Ten animals were left untreated. After a 3-week treatment period, the animals were euthanized, and the infected tibiae and implants were processed for quantitative bacterial cultures. The bacterial cultures from bones were positive for MRSA in all animals in the untreated group, the daptomycin group, and the fosfomycin group, with median bacterial counts of 2.34 × 106CFU/g bone, 1.57 × 106CFU/g bone, and 3.48 × 102CFU/g bone, respectively. In the daptomycin-fosfomycin group, 6 out of 9 animals were positive for MRSA, with a median count of 7.92 CFU/g bone. Bacterial cultures derived from the titanium wires were negative in the fosfomycin- and daptomycin-fosfomycin-treated groups. Based on bacterial counts in bones, treatment with daptomycin-fosfomycin was statistically significantly superior to all that of the other groups (P≤ 0.003). Fosfomycin was superior to daptomycin and no treatment (P< 0.0001). No development of resistance was observed in any treatment arm. The combination of daptomycin and fosfomycin demonstrated synergism against MRSA in experimental implant-associated osteomyelitis.

scholarly journals A Mutation of RNA Polymerase β′ Subunit (RpoC) Converts Heterogeneously Vancomycin-Intermediate Staphylococcus aureus (hVISA) into “Slow VISA”

2015 ◽  
Vol 59 (7) ◽  
pp. 4215-4225 ◽  
Author(s):  
Miki Matsuo ◽  
Tomomi Hishinuma ◽  
Yuki Katayama ◽  
Keiichi Hiramatsu
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Rna Polymerase ◽  
Stringent Response ◽  
Whole Genome ◽  
Multicopy Plasmid ◽  
Β Subunit ◽  
Whole Genome Analysis ◽  
Content Type ◽  
Peptidoglycan Biosynthesis

ABSTRACTVarious mutations in therpoBgene, which encodes the RNA polymerase β subunit, are associated with increased vancomycin (VAN) resistance in vancomycin-intermediateStaphylococcus aureus(VISA) and heterogeneously VISA (hVISA) strains. We reported thatrpoBmutations are also linked to the expression of the recently found “slow VISA” (sVISA) phenotype (M. Saito, Y. Katayama, T. Hishinuma, A. Iwamoto, Y. Aiba, K Kuwahara-Arai, L. Cui, M. Matsuo, N. Aritaka, and K. Hiramatsu, Antimicrob Agents Chemother 58:5024–5035, 2014,http://dx.doi.org/10.1128/AAC.02470-13). Because RpoC and RpoB are components of RNA polymerase, we examined the effect of therpoC(P440L) mutation on the expression of the sVISA phenotype in the Mu3fdh2*V6-5 strain (V6-5), which was derived from a previously reported hVISA strain with the VISA phenotype. V6-5 had an extremely prolonged doubling time (DT) (72 min) and high vancomycin MIC (16 mg/liter). However, the phenotype of V6-5 was unstable, and the strain frequently reverted to hVISA with concomitant loss of low growth rate, cell wall thickness, and reduced autolysis. Whole-genome sequencing of phenotypic revertant strain V6-5-L1 and comparison with V6-5 revealed a second mutation, F562L, inrpoC. Introduction of the wild-type (WT)rpoCgene using a multicopy plasmid resolved the sVISA phenotype of V6-5, indicating that therpoC(P440L) mutant expressed the sVISA phenotype in hVISA. To investigate the mechanisms of resistance in the sVISA strain, we independently isolated an additional 10 revertants to hVISA and VISA. In subsequent whole-genome analysis, we identified compensatory mutations in the genes of three distinct functional categories: therpoCgene itself as regulatory mutations, peptidoglycan biosynthesis genes, andrelQ, which is involved in the stringent response. It appears that therpoC(P440L) mutation causes the sVISA phenotype by augmenting cell wall peptidoglycan synthesis and through the control of the stringent response.

scholarly journals In Vitro Antifungal Combination of Flucytosine with Amphotericin B, Voriconazole, or Micafungin against Candida auris Shows No Antagonism

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
A. L. Bidaud ◽  
F. Botterel ◽  
A. Chowdhary ◽  
E. Dannaoui
Keyword(s):  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Resistant Mutants ◽  
Hospital Acquired

ABSTRACT Candida auris is an emerging, multidrug-resistant pathogen responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida species drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is, therefore, noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC ranges (geometric mean [Gmean]) of flucytosine, amphotericin B, micafungin, and voriconazole were 0.125 to 1 μg/ml (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml), and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01, and 0.5 to 1.06 for the combinations of flucytosine with amphotericin B, micafungin, and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. The combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.

scholarly journals Antibacterial Activity of Geraniol in Combination with Standard Antibiotics against Staphylococcus aureus, Escherichia coli and Helicobacter pylori

2018 ◽  
Vol 13 (7) ◽  
pp. 1934578X1801300 ◽  
Author(s):  
Subrat Kumar Bhattamisra ◽  
Chew Hui Kuean ◽  
Lee Boon Chieh ◽  
Vivian Lee Yean Yan ◽  
Chin Koh Lee ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Helicobacter Pylori ◽  
Antibacterial Activity ◽  
Synergistic Effect ◽  
Inhibitory Concentration ◽  
Therapeutic Potential ◽  
E Coli ◽  
Checkerboard Assay ◽  
H Pylori

The antibacterial activity of geraniol and its effect in combination with ampicillin, amoxicillin and clarithromycin against Staphylococcus aureus, Escherichia coli and Helicobacter pylori was tested. The minimum inhibitory concentrations (MICs) and combinatory effects of geraniol against the bacteria were assessed by using the modified broth microdilution and checkerboard assay, respectively. The combinatory effect is expressed as fractional inhibitory concentration index (FICI). The MIC of geraniol against S. aureus, E. coli and H. pylori was found to be 11200, 5600, and 7325 μg/mL, respectively. A significant synergistic effect was observed with geraniol and ampicillin against S. aureus with FICI in the range 0.19 to 0.32. Geraniol and ampicillin exhibited a partial synergistic effect against E. coli. A similar effect was observed with geraniol and clarithromycin against S. aureus. A partial synergistic effect was observed with clarithromycin and geraniol against H. pylori with the FICI value in the range 0.86 to 0.89. An additive effect was observed with geraniol and amoxicillin combination against H. pylori. However, the amoxicillin and clarithromycin dose was reduced by thirty-two fold when combined with geraniol against H. pylori. The anti- H. pylori effect of geraniol with clarithromycin and amoxicillin could be of potential interest in the treatment of H. pylori infection and associated ulcers in humans. Further, geraniol, in combination with other antibiotics, has substantial therapeutic potential against S. aureus and E.coli infection.

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