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Antimicrobial Agents and Chemotherapy

Pratyush Kumar Das, Laura Puusepp, Finny S Varghese, Age Utt, Tero Ahola, Dzmitry G Kananovich, Margus Lopp, Andres Merits, Mati Karelson
Chikungunya virus (CHIKV, genus Alphavirus) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome. Active forms of replicase enzymes are generated using the autoproteolytic activity of nsP2...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Thai-Hoang Le, Charmaine Ng, Hongjie Chen, Xin Zhu Yi, Tse Hsien Koh, Timothy Mark Sebastian Barkham, Zhi Zhou, Karina Yew-Hoong Gin
Wastewater discharged from clinical isolation and general wards at two hospitals in Singapore were examined to determine the emerging trends of antibiotic resistance (AR). We quantified the concentrations of 12 antibiotic compounds by LC-MS/MS, antibiotic resistant bacteria (ARB), class 1 integrase gene (int1), and 16 antibiotic resistant genes (ARGs) that confer resistance to 10 different clinically relevant antibiotics. A subset of 119 antibiotic resistant isolates were phylogenetically classified and tested for the presence of ARGs encoding resistance to β-lactam antibiotics (blaNDM, blaKPC, blaSHV, blaCTX-M), amikacin (aac(6')-Ib), co-trimoxazole (sul1, sul2, dfrA), ciprofloxacin (qnrA, qnrB), and the int1 Among these resistant isolates, 80...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Sumanun Suwunnakorn, Hironao Wakabayashi, Elena Rustchenko
Candida albicans is an important fungal pathogen with a diploid genome that can adapt to caspofungin, a major drug from the echinocandin class, by a reversible loss of one copy of chromosome 5 (Ch5). Here we explore a hypothesis that more than one gene for negative regulation of echinocandin tolerance is carried on Ch5. We constructed C. albicans strains that each lacked one of the following Ch5 genes: CHT2 for chitinase; PGA4 for glucanosyltransferase, and CSU51, a putative transcription factor. We demonstrate that independent deletion of each of these genes increased caspofungin and anidulafungin, another echinocandin, tolerance...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Gabriela Bergiante Kraychete, Larissa Alvarenga Batista Botelho, Eloiza Helena Campana, Renata Cristina Picão, Raquel Regina Bonelli
Plasmid-mediated qnr genes have been reported in bacteria worldwide, widely associated to other relevant determinants of resistance in multiresistance plasmids. Here, we provide an update on a previously described multiplex PCR, in order to detect all six qnr families (including qnrA, qnrS, qnrB, qnrC, qnrD and qnrVC) described until now. The proposed method makes possible the screening of these genes reducing cost and time, and may demonstrate an underestimated prevalence of the latest variants described.
October 10, 2016: Antimicrobial Agents and Chemotherapy
Thomas E Kraft, Monique R Heitmeier, Marina Putanko, Rachel L Edwards, Ma Xenia G Ilagan, Maria A Payne, Joseph M Autry, David D Thomas, Audrey R Odom, Paul W Hruz
The glucose transporter PfHT is essential to the survival of the malaria parasite Plasmodium falciparum and has been shown to be a druggable target with high potential for pharmacological intervention. Identification of compounds against novel drug targets is crucial to combating resistance against current therapeutics. Here, we describe the development of a cell-based assay system readily adaptable to high-throughput screening that directly measures compound effects on PfHT-mediated glucose transport. Intracellular glucose concentrations are detected using a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose-sensor...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Ilya A Osterman, Ekaterina S Komarova, Dmitry I Shiryaev, Ilya A Korniltsev, Irina M Khven, Dmitry A Lukyanov, Vadim N Tashlitsky, Marina V Serebryakova, Olga V Efremenkova, Yan A Ivanenkov, Alexey A Bogdanov, Petr V Sergiev, Olga A Dontsova
In order to accelerate drug discovery, a simple, reliable and cost-effective system for high-throughput identification of a potential antibiotic mechanism of action is required. To facilitate such screening of new antibiotics, we created a double reporter system for not only antimicrobial activity detection, but also for simultaneous sorting of potential antimicrobials into those that cause ribosome stalling, and others that induce SOS response due to DNA damage. In this reporter system the red fluorescent protein gene rfp was placed under the control of the SOS-inducible sulA promoter...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Tanvi Shekhar-Guturja, Walters Aji Tebung, Harley Mount, Ningning Liu, Julia R Köhler, Malcolm Whiteway, Leah E Cowen
Invasive fungal infections are a leading cause of human mortality. Effective treatment is hindered by the rapid emergence of resistance to the limited number of antifungal drugs, demanding new strategies to treat life-threatening fungal infections. Here, we explore a powerful strategy to enhance antifungal efficacy using the natural product beauvericin against leading human fungal pathogens. We found that beauvericin potentiates the activity of azole antifungals against azole-resistant Candida isolates via inhibition of multidrug efflux, and that beauvericin itself is effluxed via Yor1...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Guillaume Butler-Laporte, Matthew P Cheng, Alexandre P Cheng, Emily G McDonald, Todd C Lee
BACKGROUND: Bloodstream infections with Staphylococcus aureus are clinically significant and are often treated with empiric methicillin resistance (MRSA) coverage. However, vancomycin has associated harms. We hypothesized that MRSA screening correlated with resistance in S. aureus bacteremia and could help determine empiric vancomycin requirement. METHODS: We reviewed consecutive S. aureus bacteremias over a five-year period at two tertiary care hospitals. MRSA colonization was evaluated in three ways: as tested within 30 days of bacteremia (30-Day criteria), as tested within 30 days but accounting for any prior positive results (ever positive criteria), or if the patient was known positive with patients with unknown MRSA status being labeled negative (known positive criteria)...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Suporn Pholwat, Suzanne Stroup, Scott Heysell, Oleg Ogarkov, Svetlana Zhdanova, Girija Ramakrishnan, Eric Houpt
We studied the significance of particular eis mutations on M. tuberculosis drug resistance by using a specialized transduction strategy. Recombinant strains harboring eis mutations C-14T C-12T, and G-10A exhibited kanamycin resistance with MICs of 40, 10, and 20 μg/ml respectively, while recombinant strains harboring C-14G and C-15G were kanamycin susceptible (MIC 2.5-5 μg/ml). All of the tested eis mutants remained amikacin susceptible (MIC 0.5-4 μg/ml). The identification of specific eis mutations is needed for accurate genotypic susceptibility testing for kanamycin...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Constantin Hays, Mathilde Louis, Céline Plainvert, Nicolas Dmytruk, Gérald Touak, Patrick Trieu-Cuot, Claire Poyart, Asmaa Tazi
Group B Streptococcus (GBS) is the leading cause of neonatal invasive infections and an emerging pathogen in the elderly. Our objectives were to describe the evolution of GBS resistance to antibiotics in France and to investigate the emergence of fluoroquinolone (FQ) resistant isolates. A total of 8,757 unrelated GBS isolates were collected and tested for antibiotic susceptibility from 2007 and 2014 according to EUCAST recommendations. All isolates were susceptible to penicillin G, amoxicillin, and vancomycin...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Haiying Sun, Lillian Ting, Surendra Machineni, Jens Praestgaard, Andreas Kuemmell, Daniel S Stein, Gangadhar Sunkara, Steven J Kovacs, Stephen Villano, S Ken Tanaka
Omadacycline is a first in class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes, and atypical bacteria that is being developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of a Phase 3 tablet formulation relative to intravenous (IV) administration (and of other oral formulations relative to the Phase 3 tablet) was investigated in an open-label, randomized, four-period, crossover study in healthy subjects age 18-50 years...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Danny Tsai, Penelope Stewart, Rajendra Goud, Stephen Gourley, Saliya Hewagama, Sushena Krishnaswamy, Steven C Wallis, Jeffrey Lipman, Jason A Roberts
OBJECTIVES: There are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. METHODS: A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Patrick J McNamara, Stuart B Levy
The Food and Drug Administration (FDA) recently released a final rule to ban triclosan and 18 other antimicrobial chemicals from soaps. We applaud this rule specifically because of the associated risks that triclosan poses to the spread of antibiotic resistance throughout the environment. This persistent chemical will apply constant stress to bacteria to adapt, and behavior that promotes antibiotic resistance needs to be stopped immediately when the benefits are null.
October 10, 2016: Antimicrobial Agents and Chemotherapy
Giulia Landini, Tiziana Di Maggio, Francesco Sergio, Jean-Denis Docquier, Gian Maria Rossolini, Lucia Pallecchi
The effect of high NAC concentrations (10 and 50 mM) on antibiotic activity against 40 strains of respiratory pathogens was investigated. NAC compromised carbapenem activity (mostly imipenem and, to a lesser extent, meropenem and ertapenem) in a dose-dependent fashion. Chemical instability of carbapenems in the presence of NAC was demonstrated. With other antibiotics, 10 mM NAC had no major effects, while 50 mM NAC sporadically decreased (ceftriaxone and aminoglycosides) or increased (penicillins) antibiotic activity...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Akinobu Ito, Toru Nishikawa, Shuhei Matsumoto, Hidenori Yoshizawa, Takafumi Sato, Rio Nakamura, Masakatsu Tsuji, Yoshinori Yamano
Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the 3(rd)-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced in the iron-depleted condition where that of ceftazidime was not affected. The monitoring of [Thiazole-(14)C]-cefiderocol revealed the increased intracellular accumulation of cefiderocol in the P. aeruginosa cells incubated under iron-depleted condition compared with those incubated under iron-sufficient condition...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Hang Yang, Yongli Bi, Xiaoran Shang, Mengyue Wang, Sara B Linden, Yunpeng Li, Yuhong Li, Daniel C Nelson, Hongping Wei
Streptococcus mutans often survives as a biofilm on the tooth surface and contributes to the development of dental caries. We investigated the efficacy of ClyR, an engineered chimeolysin, against S. mutans biofilms in physiological and cariogenic conditions. Susceptibility tests showed that ClyR was active against all clinical S. mutans isolates tested as well as S. mutans biofilms that displayed resistance to penicillin. S. mutans biofilms formed on hydroxyapatite discs in physiological sugar conditions and cariogenic conditions were reduced ∼2 logs and 3 logs after treatment with 100 μg/ml ClyR, respectively...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Vincent Madelain, Jérémie Guedj, France Mentré, Thi Huyen Tram Nguyen, Frédéric Jacquot, Lisa Oestereich, Takumi Kadota, Koichi Yamada, Anne-Marie Taburet, Xavier de Lamballerie, Hervé Raoul
Favipiravir is a RNA polymerase inhibitor that showed a strong antiviral efficacy in vitro and in small animal models of several viruses responsible for hemorrhagic fever (HF) including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in non-human primates (NHP) in order to guide future efficacy studies of favipiravir in large animal models.Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n=17) or Mauritian (n=13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg BID...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Manju Bala, Vikram Singh, Aradhana Bhargava, Monika Kakran, Naveen Chandra Joshi, Ravi Bhatnagar
Antimicrobial susceptibility testing of 258 N. gonorrhoeae isolates by Etest determined that 60.1% were MDR while 5% strains had decreased susceptibility to currently recommended extended-spectrum cephalosporins (ESCs). Among these, 84.5% MDR and 76.9% strains having decreased susceptibility to ESCs were susceptible to gentamicin. No MDR isolate was resistant to gentamicin. These in vitro results suggest that gentamicin might be an effective treatment option for the MDR strains and in dual therapy for gonorrhea...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Gabriel Cabot, Carla López-Causapé, Alain A Ocampo-Sosa, Lea M Sommer, María Ángeles Domínguez, Laura Zamorano, Carlos Juan, Fe Tubau, Cristina Rodríguez, Bartolomé Moyà, Carmen Peña, Luis Martínez-Martínez, Patrick Plesiat, Antonio Oliver
Whole genome sequencing (WGS) was used for the characterization of the, frequently extensively-drug resistant (XDR), P. aeruginosa high-risk clone ST175. A total of eighteen ST175 isolates recovered from 8 different Spanish hospitals were analyzed; four isolates from four different French hospitals were included for comparison. The typical resistance profile of ST175 included penicillins, cephalosporins, monobactams, carbapenems, aminoglycosides, and fluoroquinolones. In the phylogenetic analysis, the four French isolates clustered together with the two isolates from one of the Spanish regions...
October 10, 2016: Antimicrobial Agents and Chemotherapy
Ganesh Krishnamoorthy, David Wolloscheck, Jon W Weeks, Cameron Croft, Valentin V Rybenkov, Helen I Zgurskaya
In Gram-negative bacteria, a synergistic relationship between slow passive uptake of antibiotics across the outer membrane and active efflux transporters creates a permeability barrier, which efficiently reduces effective concentrations of antibiotics in cells and hence, their activities. To analyze the relative contributions of the active efflux and the passive barrier in activities of antibiotics, we constructed Escherichia coli strains with controllable permeability of the outer membrane. The strains express a large pore that does not discriminate compounds based on their hydrophilicity and sensitizes cells to a variety of antibacterial agents...
October 3, 2016: Antimicrobial Agents and Chemotherapy
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