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ACS Infectious Diseases

Fang Liang, Daniel J Browne, Megan J Gray, Kate H Gartlan, David D Smith, Ross Barnard, Geoff R Hill, Simon Robert Corrie, Kate Markey
Blood stream infection is a significant clinical problem, particularly in vulnerable patient groups such as those undergoing chemotherapy and bone marrow transplantation. Clinical diagnostics for suspected blood stream infection remain centered around blood culture (highly variable timing, hours to days), and empiric use of broad-spectrum antibiotics is often employed for patients presenting with febrile neutropenia. Gram-typing provides the first opportunity to target therapy (e.g. combinations containing vancomycin or teicoplanin for Gram-positives; piperacillin-tazobactam or a carbapenem for Gram-negatives), however current approaches require blood culture...
January 19, 2018: ACS Infectious Diseases
Madison B Adolph, Robin P Love, Linda Chelico
The Apolipoprotein B mRNA editing complex (APOBEC) family of enzymes are single-stranded polynucleotide cytidine deaminases. These enzymes catalyze the deamination of cytidine in RNA or single-stranded DNA, which forms uracil. From this eleven member enzyme family in humans, the deamination of single-stranded DNA by the seven APOBEC3 family members are considered here. The APOBEC3 family has many roles such as, restricting endogenous and exogenous retrovirus replication and retrotransposon insertion events and reducing DNA-induced inflammation...
January 18, 2018: ACS Infectious Diseases
Ylan Nguyen, Stephen Boulton, E Tyler McNicholl, Madoka Akimoto, Hanjeong Harvey, Francisca Aidoo, Giuseppe Melacini, Lori L Burrows
Type IVa pili (T4aP) are long, thin surface filaments involved in attachment, motility, biofilm formation, and DNA uptake. They are important virulence factors for many bacteria, including Pseudomonas aeruginosa, an opportunistic pathogen and common cause of hospital-acquired infections. Each helical filament contains thousands of monomers of the major pilin subunit, PilA. Each P. aeruginosa strain expresses one of five phylogenetically distinct major pilins, which vary in sequence and the nature of their associated accessory protein(s)...
January 17, 2018: ACS Infectious Diseases
Alexander T Chao, Boon Heng Lee, Kah Fei Wan, Jeremy Selva, Bin Zou, Peter Gedeck, David Beer, Thierry T Diagana, Ghislain Bonamy, Ujjini H Manjunatha
Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and Cryptosporidium hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of their human hosts. The only approved drug for cryptosporidiosis is nitazoxanide, which shows limited efficacy in immunocompromised children, the most vulnerable patient population. Thus, new therapeutics and in vitro infection models are urgently needed to address the current unmet medical need. Toward this aim, we have developed novel cytopathic effect (CPE)-based Cp and Ch assays in human colonic tumor (HCT-8) cells and compared them to traditional imaging formats...
January 17, 2018: ACS Infectious Diseases
Leila Saxby Ross, Maria Jose Lafuente-Monasterio, Tomoyo Sakata-Kato, Rebecca E K Mandt, Francisco-Javier Gamo, Dyann F Wirth, Amanda K Lukens
Drug resistance has been reported for every antimalarial in use highlighting the need for new strategies to protect the efficacy of therapeutics in development. We have previously shown that resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another (collateral sensitivity), we can design combination therapies that not only kill the parasite, but also guide its evolution away from resistance. We applied this concept to the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme, a well validated antimalarial target with inhibitors in the development pipeline...
January 16, 2018: ACS Infectious Diseases
Leanne Barnard, Konrad Johannes Mostert, Willem A L van Otterlo, Erick Strauss
Pantothenamides (PanAms) are analogues of pantothenate, the biosynthetic precursor of coenzyme A (CoA), and show potent antimicrobial activity against several bacteria and the malaria parasite in vitro. However, pantetheinase enzymes that normally degrade pantetheine in human serum also act on the PanAms, thereby reducing their potency. In this study, we designed analogues of the known antibacterial PanAm N-heptylpantothenamide (N7-Pan) to be resistant to pantetheinase by using three complementary structural modification strategies...
January 14, 2018: ACS Infectious Diseases
María Jesus Chaparro, Felix Calderon, Pablo Castañeda, Elena Fernandez Alvaro, Raquel Gabarro, Francisco-Javier Gamo, María G Gómez-Lorenzo, Julio Martín, Esther Fernandez
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (Artemisinin Combination Therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits...
January 10, 2018: ACS Infectious Diseases
Andrew L Fraser, Stefanie K Menzies, Elizabeth F B King, Lindsay B Tulloch, Eoin R Gould, Marija Zacharova, Terry K Smith, Gordon J Florence
Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photo-affinity probes capable of labeling target protein(s) in vitro. Several of these functionalised compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major and Leishmania donovani...
January 9, 2018: ACS Infectious Diseases
Paolo Andriollo, Charlotte K Hind, Pietro Picconi, Kazi S Nahar, Shirin Jamshidi, Amrit Varsha, Melanie Clifford, J Mark Sutton, Khondaker Miraz Rahman
Antimicrobial resistance has become a major global concern. Development of novel antimicrobial agents for the treatment of infections caused by multidrug resistant (MDR) pathogens is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents initially discovered and isolated from natural sources. Recently, C8-linked PBD biaryl conjugates have been shown to be active against some MDR Gram-positive strains. To explore the role of building block orientations on antibacterial activity and obtain structure activity relationship (SAR) information, four novel structures were synthesized in which the building blocks of previously reported compounds were inverted, and their antibacterial activity was studied...
January 9, 2018: ACS Infectious Diseases
Naimee Mehta, Lori Ferrins, Susan E Leed, Richard J Sciotti, Michael P Pollastri
We recently reported the medicinal chemistry re-optimization of a known human tyrosine kinase inhibitor, lapatinib, against a variety of parasites responsible for numerous tropical diseases, including: human African trypanosomiasis (Trypanosoma brucei), Chagas disease (T. cruzi), Leishmaniasis (Leishmania spp.) and malaria (Plasmodium falciparum). Herein, we report our continuing efforts to optimize this series against P. falciparum. Through the design of a library of compounds focused on reducing the lipophilicity and molecular weight, followed by an SAR exploration, we have identified NEU-1953 (40)...
January 4, 2018: ACS Infectious Diseases
Maya A Farha, Shawn French, Jonathan M Stokes, Eric D Brown
The antibacterial properties of sodium bicarbonate have been known for years, yet the molecular understanding of its mechanism of action is still lacking. Utilizing chemical-chemical combinations, we first explored the effect of bicarbonate on the activity of conventional antibiotics to infer on the mechanism. Remarkably, the activity of 8 classes of antibiotics differed in the presence of this ubiquitous buffer. These interactions and a study of mechanism of action revealed that, at physiological concentrations, bicarbonate is a selective dissipater of the pH gradient of the proton motive force across the cytoplasmic membrane of both Gram-negative and Gram-positive bacteria...
January 4, 2018: ACS Infectious Diseases
Stanford Schor, Shirit Einav
There is a large, global unmet need for the development of countermeasures to combat intracellular pathogens. The development of novel antimicrobials is expensive and slow and typically focuses on selective inhibition of proteins encoded by a single pathogen, thereby providing a narrow spectrum of coverage. The repurposing of approved drugs targeting host functions required for microbial infections represents a promising alternative. This review summarizes progress and challenges in the repurposing of approved drugs as host-targeted broad-spectrum agents for the treatment of intracellular pathogens...
January 3, 2018: ACS Infectious Diseases
Heidi Wolfmeier, Daniel Pletzer, Sarah C Mansour, Robert E W Hancock
Microbial biofilms, which are elaborate and highly resistant microbial aggregates formed on surfaces or medical devices, cause two-thirds of infections and constitute a serious threat to public health. Immunocompromised patients, individuals who require implanted devices, artificial limbs, organ transplants, or external life support and those with major injuries or burns, are particularly prone to become infected. Antibiotics, the mainstay treatments of bacterial infections, have often proven ineffective in the fight against microbes when growing as biofilms, and to date, no antibiotic has been developed for use against biofilm infections...
December 27, 2017: ACS Infectious Diseases
Ramkumar Iyer, Samir H Moussa, Thomas F Durand-Réville, Ruben Tommasi, Alita Miller
OmpAAb is a conserved, abundantly expressed outer membrane porin in Acinetobacter baumannii whose presumed role in antibiotic permeation has not been clearly demonstrated. In this report, we use a titratable heterologous expression system to express OmpAAb in isolation and demonstrate selective passage of small molecule antibiotics through OmpAAb. ETX2514, a recently discovered broad-spectrum β-lactamase inhibitor, in combination with sulbactam, is currently in clinical testing for the treatment of drug-resistant A...
December 26, 2017: ACS Infectious Diseases
Charlie Y Mo, Matthew J Culyba, Trevor Selwood, Jeffrey M Kubiak, Zachary M Hostetler, Anthony J Jurewicz, Paul M Keller, Andrew J Pope, Amy Quinn, Jessica L Schneck, Katherine L Widdowson, Rahul M Kohli
The RecA/LexA axis of the bacterial DNA damage (SOS) response is a promising, yet non-traditional drug target. The SOS response is initiated upon genotoxic stress, when RecA, a DNA damage sensor, induces LexA, the SOS repressor, to undergo autoproteolysis, thereby de-repressing downstream genes that can mediate DNA repair and accelerate mutagenesis. As genetic inhibition of the SOS response sensitizes bacteria to DNA damaging antibiotics and decreases acquired resistance, inhibitors of the RecA/LexA axis could potentiate our current antibiotic arsenal...
December 24, 2017: ACS Infectious Diseases
Christopher M Rath, Bret M Benton, Javier de Vicente, Joseph E Drumm, Mei Geng, Cindy Li, Robert J Moreau, Xiaoyu Shen, Colin K Skepper, Micah Steffek, Kenneth Takeoka, Lisha Wang, Jun-Rong Wei, Wenjian Xu, Qiong Zhang, Brian Y Feng
Drug-resistant Gram-negative bacteria are of increasing concern worldwide. Novel antibiotics are needed, but their development is complicated by the requirement to simultaneously optimize molecules for target affinity and cellular potency, which can result in divergent structure-activity relationships (SARs). These challenges were exemplified during our attempts to optimize inhibitors of the bacterial enzyme CoaD originally identified through a biochemical screen. To facilitate lead optimization, we developed mass spectroscopy assays based on the hypothesis that levels of CoA metabolites would reflect the cellular enzymatic activity of CoaD...
December 22, 2017: ACS Infectious Diseases
Kris M White, Pablo Abreu, Hui Wang, Paul D De Jesus, Balaji Manicassamy, Adolfo García-Sastre, Sumit K Chanda, Robert J DeVita, Megan L Shaw
S119 was a top hit from an ultra-high through-put screen performed to identify novel inhibitors of influenza virus replication. It showed a potent antiviral effect (IC50 = 20 nM) and no detectable cytotoxicity (CC50 >500 μM) to yield a selectivity index greater than 25,000. Upon investigation, we found that S119 selected for resistant viruses carrying mutations in the viral nucleoprotein (NP). These resistance mutations highlight a likely S119 binding site overlapping with, but not identical to that found for the compound nucleozin...
December 21, 2017: ACS Infectious Diseases
Eugen Franz, Matthias J Knape, Friedrich W Herberg
cGMP-dependent protein kinase from Plasmodium falciparum (PfPKG) plays a crucial role in the sexual as well as the asexual proliferation of this human malaria causing parasite. However, function and regulation of PfPKG are largely unknown. Previous studies showed that the domain organization of PfPKG significantly differs from human PKG (hPKG) and indicated a critical role of the cyclic nucleotide binding domain D (CNB D). We identified a novel mechanism, where the CNB-D controls activation and regulation of the parasite specific protein kinase...
December 18, 2017: ACS Infectious Diseases
Amy E Solinski, Cristian Ochoa, Young Eun Lee, Thomas Paniak, Marisa C Kozlowski, William M Wuest
The oral microbiome is a complex ecological niche where both commensal and pathogenic bacteria coexist. Previous reports have cited that the plant isolate honokiol is a potent inhibitor of S. mutans biofilms. Herein we report a cross-coupling method that provides access to a concise library of honokiol-inspired analogs. Through this work we determined that the inhibitory activity of honokiol is highly dependent on the growth conditions. Further, we identify a series of analogs that display significant potency against oral bacteria leading to the discovery of a potent antimicrobial...
December 13, 2017: ACS Infectious Diseases
Abraham J Waldman, Emily P Balskus
Despite significant advances in treating infectious diseases worldwide, morbidity and mortality associated with pathogen infection remains extraordinarily high and represents a critical scientific and global health challenge. Current strategies to combat these infectious agents include a combination of vaccines, small molecule drugs, increased hygiene standards, and disease-specific interventions. While these approaches have helped to drastically reduce the incidence and number of deaths associated with infection, continued investment in current strategies and the development of novel therapeutic approaches will be required to address these global health threats...
December 13, 2017: ACS Infectious Diseases
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