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Antimicrobial Agents and Chemotherapy

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https://www.readbyqxmd.com/read/28223393/novel-bacterial-topoisomerase-inhibitors-with-potent-broad-spectrum-activity-against-drug-resistant-bacteria
#1
Cédric Charrier, Anne-Marie Salisbury, Victoria J Savage, Thomas Duffy, Emmanuel Moyo, Nathan Chaffer-Malam, Nicola Ooi, Rebecca Newman, Jonathan Cheung, Richard Metzger, David McGarry, Mark Pichowicz, Ralph Sigerson, Ian R Cooper, Gary Nelson, Hayley S Butler, Mark Craighead, Andrew J Ratcliffe, Stuart A Best, Neil R Stokes
The Novel Bacterial Topoisomerase Inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that do not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecules. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms, and Mycobacterium tuberculosis No cross-resistance with quinolone-resistant Staphylococcus aureus and E...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223392/streptococcus-mitis-and-s-oralis-lack-a-requirement-for-cdsa-the-enzyme-required-for-synthesis-of-major-membrane-phospholipids-in-bacteria
#2
Hannah M Adams, Luke R Joyce, Ziqiang Guan, Ronda L Akins, Kelli L Palmer
Synthesis and integrity of the cytoplasmic membrane is fundamental to cellular life. Experimental evolution studies have hinted at unique physiology in the Gram-positive bacteria Streptococcus mitis and S. oralis These organisms commonly cause bacteremia and infectious endocarditis (IE) but are rarely investigated in mechanistic studies of physiology and evolution. Unlike other Gram-positive pathogens, high-level (MIC ≥ 256 μg/mL) daptomycin resistance rapidly emerges in S. mitis and S. oralis after a single drug exposure...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223391/evaluation-of-para-aminosalicylic-acid-pas-as-a-substrate-of-multiple-solute-carrier-slc-uptake-transporters-and-possible-drug-interactions-with-nsaids-in-vitro
#3
Md Masud Parvez, Ho Jung Shin, Jin Ah Jung, Jae-Gook Shin
para-Aminosalicylic acid (PAS) is a second-line anti-tuberculosis drug used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters, and found that PAS acts as a novel substrate of organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but not a substrate of any ATP-binding cassette (ABC) transporters...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223390/expression-of-the-aac-6-ib-cr-gene-in-class-1-integrons
#4
Sophie Raherison, Thomas Jove, Margaux Gaschet, Emilie Pinault, Aurore Tabesse, Carmen Torres, Marie-Cécile Ploy
The aac(6')-Ib-cr is a plasmid-mediated quinolone resistance (PMQR) gene embedded within a gene cassette, most often within an integron. It confers resistance to both quinolones and aminoglycosides. We investigated the role of a 101-bp fragment frequently present upstream of the aac(6')-Ib-cr gene cassette and found it contributes to the expression of aac(6')-Ib-cr and provides an alternative START codon confirming the length of the AAC(6')-Ib-cr protein to 199-aa.
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223389/analysis-of-serial-isolates-of-mcr-1-positive-escherichia-coli-reveals-a-highly-active-isapl1-transposon
#5
Erik Snesrud, Ana C Ong, Brendan Corey, Yoon I Kwak, Robert Clifford, Todd Gleeson, Shannon Wood, Timothy J Whitman, Emil P Lesho, Mary Hinkle, Patrick Mc Gann
The emergence of the transferable colistin resistance gene mcr-1 is of global concern. The insertion sequence (IS) Apl1 is a key component in the mobilization of this gene, but its role remains poorly understood.Six Escherichia coli were cultured from the same patient over one month in Germany and the USA after a brief hospitalization in Bahrain for an unconnected illness. Four carried mcr-1 by real-time PCR, but two were negative. Two additional mcr-1-negative E. coli were collected during follow-up surveillance nine months later...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223388/in-vitro-and-in-vivo-antifungal-profile-of-a-novel-and-long-acting-inhaled-azole-pc945-on-aspergillus-fumigatus-infection
#6
Thomas Colley, Alexandre Alanio, Steven L Kelly, Gurpreet Sehra, Yasuo Kizawa, Andrew G S Warrilow, Josie E Parker, Diane E Kelly, Genki Kimura, Lauren Anderson-Dring, Takahiro Nakaoki, Mihiro Sunose, Stuart Onions, Damien Crepin, Franz Lagasse, Matthew Crittall, Jonathan Shannon, Michael Cooke, Stéphane Bretagne, John King-Underwood, John Murray, Kazuhiro Ito, Pete Strong, Garth Rapeport
The profile of PC945, a novel triazole antifungal, designed for administration via inhalation, has been assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tight-binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (IC50, 0.23 μM and 0.22 μM, respectively), with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032∼>8 μg/ml, whilst those of voriconazole ranged from 0...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223387/activity-of-sanguinarine-against-candida-albicans-biofilms
#7
Hua Zhong, Dan-Dan Hu, Gan-Hai Hu, Juan Su, Shuang Bi, Zhuo-Er Zhang, Zheng Wang, Ri-Li Zhang, Zheng Xu, Yuan-Ying Jiang, Yan Wang
C. albicans biofilms show resistance to many clinical antifungal agents, and play a considerable contributing role in the process of C. albicans infections. New antifungal agents against C. albicans biofilms are sorely needed. The aim of this study was to evaluate sanguinarine (SAN) for its activity against Candida albicans biofilms and explore the underlying mechanism. The MIC50 of SAN was 3.2 μg/mL. While ≥ 0.8 μg/mL SAN could suppress C. albicans biofilms. Further mechanism study revealed that ≥ 0...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223386/surveillance-of-omadacycline-activity-tested-against-clinical-isolates-from-a-global-north-america-europe-latin-america-and-asia-western-pacific-collection-2010-2011
#8
Michael A Pfaller, Michael D Huband, Paul R Rhomberg, Robert K Flamm
Omadacycline is a broad spectrum aminomethylcycline in late-stage clinical development for acute bacterial skin and skin structure infections and community-acquired pneumonia as both an oral and intravenous, once-daily formulation. In this report omadacycline and comparators were tested against 69,246 non-duplicate bacterial isolates collected prospectively during 2010 and 2011 from medical centers in Asia-Pacific (11,397 isolates), Europe (23,490 isolates), Latin America (8,038 isolates) and North America (26,321 isolates)...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223385/deletion-of-nudb-causes-increased-susceptibility-to-antifolates-in-escherichia-coli-and-salmonella-enterica
#9
Kun Li, Ting Li, Shan-Shan Yang, Xu-De Wang, Lei-Xin Gao, Rui-Qi Wang, Jing Gu, Xian-En Zhang, Jiao-Yu Deng
Co-trimoxazole, a fixed-dose combination of sulfamethoxazole (SMX) and trimethoprim (TMP), has been used for the treatment of bacterial infections since the 1960s. Since it has long been assumed that the synergistic effects between SMX and TMP are the consequence of targeting 2 different enzymes of bacterial folate biosynthesis, 2 genes (pabB and nudB) involved in the folate biosynthesis of Escherichia coli were deleted, and their effects on the susceptibility to antifolates were tested. The results showed that the deletion of nudB resulted in a lag of growth in minimal medium, and increased susceptibility to both SMX and TMP...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223384/tolerance-to-caspofungin-in-candida-albicans-is-associated-with-at-least-three-distinctive-mechanisms-that-govern-expression-of-fks-genes-and-cell-wall-remodeling
#10
Feng Yang, Lulu Zhang, Hironao Wakabayashi, Jason Myers, Yuanying Jiang, Yongbing Cao, Cristina Jimenez-Ortigosa, David S Perlin, Elena Rustchenko
Expanding echinocandin use to prevent or treat invasive fungal infections has led to an increase in the number of breakthrough infections due to resistant Candida species. Although uncommon, echinocandin resistance is well documented for Candida albicans, which is among the most prevalent bloodstream organisms. A better understanding is needed to assess the cellular factors that promote tolerance and predispose infecting cells for clinical breakthrough. We have previously showed that some mutants adapted to growth in the presence of toxic sorbose due to loss of one chromosome 5 (Ch5) also became more tolerant to caspofungin...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223383/requirement-of-the-crors-two-component-system-for-resistance-to-cell-wall-targeting-antimicrobials-in-enterococcus-faecium
#11
Stephanie L Kellogg, Jaime L Little, Jessica S Hoff, Christopher J Kristich
Enterococci are serious opportunistic pathogens that are resistant to many cell-wall-targeting antibiotics. The CroRS two-component signaling system responds to antibiotic-mediated cell-wall stress and is critical for resistance to cell-wall-targeting antibiotics in Enterococcus faecalis Here, we identify and characterize an orthologous two-component system found in Enterococcus faecium that is functionally equivalent to the CroRS system of E. faecalis Deletion of croRS in E. faecium resulted in marked susceptibility to cell-wall-targeting agents including cephalosporins and bacitracin, as well as moderate susceptibility to ampicillin and vancomycin...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223382/in-vitro-and-in-vivo-activity-of-omadacycline-against-two-biothreat-pathogens-bacillus-anthracis-and-yersinia-pestis
#12
Judith Steenbergen, S Ken Tanaka, Lynda L Miller, Stephanie A Halasohoris, Jeremy R Hershfield
Introduction: The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis, respectively.Methods: Minimum inhibitory concentrations (MICs) of OMC were determined by microbroth dilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis The in vivo efficacy of omadacycline was studied at a range of dosages in both a post exposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223381/a-phase-i-randomized-double-blinded-placebo-and-moxifloxacin-controlled-4-period-crossover-study-to-evaluate-the-effect-of-gepotidacin-on-cardiac-conduction-as-assessed-by-12-lead-electrocardiogram-in-healthy-volunteers
#13
Mohammad Hossain, Meijian Zhou, Courtney Tiffany, Etienne Dumont, Borje Darpo
Gepotidacin is a novel, first in class triazaacenaphthylene antibiotic in development for treatment of conventional and biothreat infections. This was a single-dose, cross-over thorough QT study in healthy subjects who were administered an IV gepotidacin as a therapeutic (1000 mg), and supra-therapeutic (1800 mg) dose, placebo and 400 mg oral moxifloxacin in 4 separate treatment periods.Gepotidacin caused a mild effect on heart rate with a largest placebo-corrected change-from-baseline HR of 7 and 10 bpm at the end of the 1000 mg and 1800 mg infusion, respectively...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223380/vitamin-k3-induces-the-expression-of-the-stenotrophomonas-maltophilia-smevwx-multidrug-efflux-pump
#14
P Blanco, F Corona, M B Sánchez, J L Martínez
Stenotrophomonas maltophilia is an opportunistic pathogen, with increasing prevalence, able to cause infections in immunocompromised patients or in those with a previous pathology. The treatment of the infections caused by this bacterium is often complicated due to the several intrinsic antibiotic resistance mechanisms that it presents. Multidrug efflux pumps are among the best studied mechanisms of S. maltophilia antibiotic resistance. Some of these efflux pumps have a basal expression level but, in general, their expression is often low and only reaches high levels when the local regulator is mutated or bacteria are in the presence of an effector...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223379/mutations-in-blakpc-3-that-confer-ceftazidime-avibactam-resistance-encode-novel-kpc-3-variants-that-function-as-extended-spectrum-%C3%AE-lactamases
#15
Ghady Haidar, Cornelius J Clancy, Ryan K Shields, Binghua Hao, Shaoji Cheng, M Hong Nguyen
We identified four blaKPC-3 mutations in ceftazidime-avibactam resistant clinical Klebsiella pneumoniae isolates, corresponding to D179Y, T243M, D179Y/T243M, and EL165 KPC-3 variants. Using site-directed mutagenesis and transforming vectors into Escherichia coli, we conclusively demonstrated that mutant blaKPC-3 encoded enzymes that functioned as extended-spectrum β-lactamases; mutations directly conferred higher MICs of ceftazidime-avibactam MICs, and decreased MICs of carbapenems and other β-lactams. Impact was strongest for the D179Y mutant, highlighting the importance of the KPC Ω-loop...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223378/population-pharmacokinetic-analysis-of-doripenem-after-intravenous-infusion-in-korean-patients-with-acute-infections
#16
Dong-Hwan Lee, Yong Kyun Kim, Kyubok Jin, Myoung Joo Kang, Young-Don Joo, Yang Wook Kim, Young Soo Moon, Jae-Gook Shin, Sungmin Kiem
We investigated population pharmacokinetics (PK) of doripenem in Korean patients with acute infections, and determined an appropriate dosing regimen using a Monte-Carlo simulation for predicting pharmacodynamics (PD). Patients (n = 37) with a creatinine clearance (CLCR) of 20∼50 mL/min or >50 mL/min who received a 250-mg or 500-mg dose of doripenem over the course of one hour every eight hours, respectively, were included in this study. Blood samples were taken pre-dose and 0 h, 0.5 h, and 4-6 h after the fourth infusion...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223377/exopolysaccharide-repressing-small-molecules-with-antibiofilm-and-antivirulence-activity-against-pseudomonas-aeruginosa
#17
Erik van Tilburg Bernardes, Laetitia Charron-Mazenod, David J Reading, Shauna L Reckseidler-Zenteno, Shawn Lewenza
Biofilm formation is a universal virulence strategy in which bacteria grow in dense microbial communities enmeshed within a polymeric extracellular matrix that protects them from antibiotic exposure and the immune system. Pseudomonas aeruginosa is an archetypal biofilm-forming organism that utilizes a biofilm growth strategy to cause chronic lung infections in Cystic Fibrosis (CF) patients. The extracellular matrix of P. aeruginosa biofilms is comprised mainly of exopolysaccharides (EPS) and DNA. Both mucoid and non-mucoid isolates of P...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223376/bactericidal-and-fungicidal-activity-of-n-chlorotaurine-is-enhanced-in-cystic-fibrosis-sputum-medium
#18
Martina Gruber, Ivan Moser, Markus Nagl, Michaela Lackner
Lung infections with multiresistant pathogens are a major problem of patients suffering from cystic fibrosis (CF). N-chlorotaurine (NCT), a microbicidal active chlorine compound with no resistance development, is well tolerated upon inhalation. The aim of this study was to investigate NCT on its bactericidal and fungicidal activity in vitro in artificial sputum medium (ASM) mimicking the composition of cystic fibrosis mucus.The medium was inoculated with bacteria (Staphylococcus aureus including some MRSA strains, Pseudomonas aeruginosa, Escherichia coli) or spores of fungi (Aspergillus fumigatus, Aspergillus terreus, Candida albicans, Scedosporium apiospermum, Scedosporium boydii, Lomentospora prolificans, Scedosporium aurantiacum, Scedosporium minutisporum, Exophiala dermatitidis, Geotrichum sp...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223375/the-emerging-candida-auris-characterization-of-growth-phenotype-virulence-factors-antifungal-activity-and-effect-of-scy-078-a-novel-glucan-synthesis-inhibitor-on-growth-morphology-and-biofilm-formation
#19
Emily Larkin, Christopher Hager, Jyotsna Chandra, Pranab K Mukherjee, Mauricio Retuerto, Iman Salem, Lisa Long, Nancy Isham, Laura Kovanda, Katyna Borroto-Esoda, Steve Wring, David Angulo, Mahmoud Ghannoum
The Center for Disease Control and Prevention recently alerted that emerging multidrug-resistant Candida auris is causing invasive infections (1).….
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28223374/enterobacter-cloacae-complex-isolates-harboring-blanmc-a-or-blaimi-type-class-a-carbapenemase-genes-on-novel-chromosomal-integrative-elements-and-plasmids
#20
David A Boyd, Laura F Mataseje, Ross Davidson, Johannes A Delport, Jeff Fuller, Linda Hoang, Brigitte Lefebvre, Paul Levett, Diane L Roscoe, Barbara M Willey, Michael R Mulvey
Carbapenem-resistant Enterobacter cloacae complex isolates submitted to a reference laboratory from 2010 to 2015 were screened by PCR for seven common carbapenemase gene groups, namely, KPC, NDM, OXA-48, VIM, IMP, GES, and NMC-A/IMI. Nineteen of the submitted isolates (1.7%) were found to harbor Ambler class A blaNMC-A or blaIMI-type carbapenemases. All 19 isolates were resistant to at least one carbapenem but susceptible to aminoglycosides, trimethoprim-sulfamethoxazole, tigecycline, and ciprofloxacin. Most isolates (17/19) gave positive results with the Carba-NP test for phenotypic carbapenemase detection...
February 21, 2017: Antimicrobial Agents and Chemotherapy
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