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ACS Infectious Diseases

Lola Fagbami, Amy A Deik, Jonathan D Herman, Kritika Singh, Sofia A Santos, Selina Bopp, Amanda K Lukens, Clary B Clish, Dyann F Wirth, Ralph Mazitschek
We have previously identified the cytoplasmic prolyl tRNA synthetase in Plasmodium falciparum as the functional target of the natural product febrifugine and its synthetic analogue halofuginone (HFG), one of the most potent antimalarials discovered to date. However, our studies also discovered that short-term treatment of asexual blood stage P. falciparum with HFG analogues causes a 20-fold increase in intracellular proline, termed Adaptive Proline Response (APR), which renders parasites tolerant to HFG. This novel resistance phenotype lacks an apparent genetic basis but remains stable after drug withdrawal...
February 18, 2019: ACS Infectious Diseases
Yameng Pei, Chunting Wang, Haijing Ben, Lei Wang, Yao Ma, Qingyan Ma, Ye Xiang, Linqi Zhang, Gang Liu
In this article, a simple and effective high-throughput screening (HTS) assay was developed to identify anti-HBV compounds by using a HepAD38 luciferase reporter (HepAD38-luc) cell line that can effectively exclude the false positive hit compounds targeted on the tetracycline off (tet-off) regulation system. Through screening in-house chemical libraries, N-phenylpiperidine-3-carboxamide derivatives, represented by 1 and 2 were identified, while the other false positive hits, i. e. quinoxaline (3) and benzothiazin (4) derivatives were simultaneously excluded...
February 14, 2019: ACS Infectious Diseases
Elizabeth G Gibson, Ben Bax, Pan F Chan, Neil Osheroff
Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI). The compound has successfully completed phase II trials for the treatment of acute bacterial skin/skin structure infections and for the treatment of uncomplicated urogenital gonorrhea. It also displays robust in vitro activity against a range of wild-type and fluoroquinolone-resistant bacteria. Due to the clinical promise of gepotidacin, a detailed understanding of its interactions with its antibacterial targets is essential...
February 13, 2019: ACS Infectious Diseases
Briana Flaherty, Tienhuei G Ho, Sven Schmidt, Friedrich W Herberg, David Peterson, Eileen Kennedy
To explore the possibility of constrained peptides to target Plasmodium-infected cells, we designed a J domain mimetic derived from Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) as a strategy to disrupt J domain binding and inhibit PfCDPK1 activity. The J domain disruptor (JDD) peptide was conformationally constrained using a hydrocarbon staple and was found to selectively permeate segmented schizonts and colocalize with intracellular merozoites in late-stage parasites. In vitro analyses demonstrated that JDD could effectively inhibit the catalytic activity of recombinant PfCDPK1 in the low micromolar range...
February 12, 2019: ACS Infectious Diseases
Minhee Lee, Jinshi Zhao, Seung-Hwa Kwak, Jae Cho, Myungju Lee, Robert A Gillespie, Do-Yeon Kwon, Hyunji Lee, Hyun-Ju Park, Qinglin Wu, Pei Zhou, Jiyong Hong
The UDP-2,3-diacylglucosamine pyrophosphatase LpxH in the Raetz pathway of lipid A biosynthesis is an essential enzyme in the vast majority of Gram-negative pathogens and an excellent novel antibiotic target. The 32 P-radioautographic thin-layer chromatography assay has been widely used for analysis of LpxH activity, but it is inconvenient for evaluation of a large number of LpxH inhibitors over an extended time period. Here, we report a coupled, nonradioactive LpxH assay that utilizes the recently discovered Aquifex aeolicus lipid A 1-phosphatase LpxE for quantitative removal of the 1-phosphate from lipid X, the product of the LpxH catalysis; the released inorganic phosphate is subsequently quantified by the colorimetric malachite green assay, allowing the monitoring of the LpxH catalysis...
February 5, 2019: ACS Infectious Diseases
Kang Xiong-Hang, Kaila Kemnetz-Ness, Anna Krieger, Christy L Haynes
Platelets are anuclear circulating cell bodies within the bloodstream commonly known for their roles in clot formation during vascular injury to prevent blood loss. They also have significant impact in a range of diseases, including malaria. However, the role of platelets in malaria is controversial, with contradicting evidence suggesting either that they assist in destruction of malarial parasites or facilitate a severe form of malaria. Precedent work suggests that the timing of infection is critical in determining whether platelets switch roles from being protective to deleterious...
February 3, 2019: ACS Infectious Diseases
Samantha N Muellers, Juliana A Gonzalez, Abinash Kaur, Vital Sapojnikov, Annie Laurie Benzie, Dean G Brown, David W Parkin, Brian J Stockman
Trichomoniasis is caused by the parasitic protozoan Trichomonas vaginalis and is the most prevalent, nonviral sexually transmitted disease. The parasite has shown increasing resistance to the current 5-nitroimidazole therapies indicating the need for new therapies with different mechanisms. T. vaginalis is an obligate parasite that scavenges nucleosides from host cells and then uses salvage pathway enzymes to obtain the nucleobases. The adenosine/guanosine preferring nucleoside ribohydrolase was screened against a 2000-compound diversity fragment library using a 1 H NMR-based activity assay...
February 1, 2019: ACS Infectious Diseases
Cristina Penaranda, Deborah T Hung
Host-pathogen interactions, particularly in the context of bacterial infections, are dynamic exchanges where transcriptional heterogeneity from both the host and the pathogen can lead to many diverse outcomes via distinct molecular pathways. Transcriptional profiling at the single-cell level, on a genome-wide scale, has enabled a greater appreciation of the cellular diversity in complex biological organisms and the myriad of host transcriptional states during infection. Here, we highlight recent reports of single-cell RNA sequencing within the context of host-pathogen interactions, describe current limitations for detecting and profiling the transcriptome of invading pathogens at the single-cell level, and suggest exciting future prospects for this technology in the study of infection...
January 31, 2019: ACS Infectious Diseases
Marcella Widya, William D Pasutti, Meena Sachdeva, Robert L Simmons, Pramila Tamrakar, Thomas Krucker, David A Six
The Gram-negative bacterial permeability barrier, coupled with efflux, raises formidable challenges to antibiotic drug discovery. The absence of efficient assays to determine compound penetration into the cell and impact of efflux makes the process resource-intensive, small-scale, and lacking much success. Here, we present BacPK: a label-free, solid phase extraction-mass spectrometry (SPE-MS)-based assay that measures total cellular compound accumulation in Escherichia coli. The BacPK assay is a 96-well accumulation assay that takes advantage of 9 s/sample SPE-MS throughput...
January 30, 2019: ACS Infectious Diseases
Ana Carolina Cauz, Gustavo Penteado Battesini Carretero, Greice Kelle Viegas Saraiva, Peter Park, Laura Mortara, Iolanda Midea Cuccovia, Marcelo Brocchi, Frederico Gueiros Filho
Violacein is a tryptophan-derived purple pigment produced by environmental bacteria which displays multiple biological activities, including strong inhibition of Gram-positive pathogens. Here we applied a combination of experimental approaches to identify the mechanism by which violacein kills Gram positive bacteria. Fluorescence microscopy showed that violacein quickly and dramatically permeabilizes B. subtilis and S. aureus cells. Cell permeabilization was accompanied by the appearance of visible discontinuities or rips in the cytoplasmic membrane, but it did not affect the cell wall...
January 29, 2019: ACS Infectious Diseases
Junnan Fang, Xuping Jing, Guoliang Lu, Yi Xu, Peng Gong
Zika virus (ZIKV), a positive-strand RNA virus belonging to the Flavivirus genus, has become an urgent public health concern since recent outbreaks worldwide. Its genome replication is facilitated by the viral NS3 protein bearing helicase function. The NS3 helicase uses energy derived from adenosine triphosphate (ATP) hydrolysis to unwind RNA duplexed regions. Structural studies of the flavivirus NS3 helicases have suggested a conserved mechanism of ATP hydrolysis. However, the process of the reactant water replenishment, a key part of the hydrolysis cycle, remains elusive...
January 28, 2019: ACS Infectious Diseases
Wenhe Zhong, Ann Koay, Anna Ngo, Yan Li, Qianhui Nah, Yee Hwa Wong, Yok Hian Chionh, Hui Qi Ng, Xiaoying Koh-Stenta, Anders Poulsen, Klement Foo, Megan McBee, Meng Ling Choong, Abbas El Sahili, Congbao Kang, Alex Matter, Julien Lescar, Jeffrey Hill, Peter C Dedon
Bacterial tRNA modification synthesis pathways are critical to cell survival under stress and thus represent ideal mechanism-based targets for antibiotic development. One such target is the tRNA-(N1 G37) methyltransferase (TrmD), which is conserved and essential in many bacterial pathogens. Here we developed and applied a widely applicable, radioactivity-free, bioluminescence-based high-throughput screen (HTS) against 116,350 compounds from structurally diverse small-molecule libraries to identify inhibitors of Pseudomonas aeruginosa TrmD ( PaTrmD)...
January 25, 2019: ACS Infectious Diseases
Yagya Prasad Subedi, Paul Roberts, Michelle Grilley, Jon Y Takemoto, Cheng-Wei Tom Chang
Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure-activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans and several Candida sp...
January 23, 2019: ACS Infectious Diseases
Dilip Menon, Kaurab Singh, Sneha M Pinto, Ananya Nandy, Neetika Jaisinghani, Rintu Kutum, Debasis Dash, Ts Keshava Prasad, Sheetal Gandotra
Growing evidence suggests the importance of lipid metabolism in pathogenesis of tuberculosis. Neutral lipids form the majority of lipids in a caseous granuloma, pathology characteristic of tuberculosis. Cytosolic lipid droplets (LDs) of macrophages form the store house of these lipids, and have been demonstrated to contribute to the inflammatory response to infection. The proteome of lipid droplets reflects the mechanisms of lipid metabolism active under a condition. However, infection induced changes in the proteome of these dynamic organelles remains elusive...
January 21, 2019: ACS Infectious Diseases
Matthew R Bockman, Curtis A Engelhart, Julia D Cramer, Michael Howe, Neeraj Mishra, Matthew Zimmerman, Peter Larson, Nadine Alvarez-Cabrera, Sae Woong Park, Helena I M Boshoff, James M Bean, Victor Young, David M Ferguson, Veronique Dartois, Joseph T Jarrett, Dirk Schnappinger, Courtney C Aldrich
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(-)-acidomycin is described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (MICs = 0.096-6.2 µM), but is inactive against non-tuberculosis mycobacteria, gram-positive and gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a Ki of approximately 1 µM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosylmethionine (SAM) to generate the toxic metabolite 5'-deoxyadenosine...
January 17, 2019: ACS Infectious Diseases
Suyash Bhatnagar, Sezin Nicklas, Joanne M Morrisey, Daniel E Goldberg, Akhil Vaidya
Lipid homeostasis is essential for the maintenance of life. We previously reported that disruptions of the parasite Na+ homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na+ homeostasis. We screened 800 compounds from the Malaria and Pathogen Boxes to identify chemotypes that disrupted the parasite plasma membrane lipid homeostasis. Here, we show that the compounds disrupting parasite Na+ homeostasis also induced saponin sensitivity, an indication of parasite lipid homeostasis disruption...
January 14, 2019: ACS Infectious Diseases
Francisca Hildemagna Guedes da Silva, Denise da Gama Jaén Batista, Cristiane França Da Silva, Beatriz Philot Pavão, Marcos Meuser Batista, Otacílio Da Cruz Moreira, Letícia Rocha Q Souza, Constança Britto, Girish Rachakonda, Fernando Villalta, Galina I Lepesheva, Maria de Nazaré Correia Soeiro
Up to now, no vaccines are available for Chagas disease, and the current therapy is largely unsatisfactory. Novel imidazole-based scaffolds of protozoan sterol 14α-demethylase (CYP51) inhibitors have demonstrated potent anti-parasitic activity with no acute toxicity. Presently our aim was to investigate the effectiveness of the experimental 14α-demethylase inhibitor VFV in the mouse models of Trypanosoma cruzi infection using naturally drug-resistant Colombiana strain, under monotherapy and in association with the reference drug, benznidazole (Bz)...
January 9, 2019: ACS Infectious Diseases
Clayton Evert, Tina Loesekann, Ganapati Bhat, Asif Shajahan, Roberto Sonon, Parastoo Azadi, Ryan Hunter
Stable isotope probing (SIP) has emerged as a powerful tool to address key questions about microbiota structure and function. To date, diverse isotopically labeled substrates have been used to characterize in situ growth activity of specific bacterial taxa and have revealed the flux of bio-available substrates through microbial communities associated with health and disease. A major limitation to the growth of the field is the dearth of biologically-relevant 'heavy' labeled substrates. Mucin glycoproteins, for example, comprise an abundant source of carbon in the gut, oral cavity, respiratory tract and other mucosal surfaces, but are not commercially available...
January 9, 2019: ACS Infectious Diseases
Panagiotis Kondylis, Christopher J Schlicksup, Sarah P Katen, Lye Siang Lee, Adam Zlotnick, Stephen C Jacobson
The self-assembly of virus capsids is a potential target for antivirals due to its importance in the virus lifecycle. Here, we investigate the effect of phenylpropenamide derivatives B-21 and AT-130 on the assembly of hepatitis B virus (HBV) core protein. Phenylpropenamides are widely believed to yield assembly of spherical particles resembling native, empty HBV capsids. Because the details of assembly can be overlooked with ensemble measurements, we performed resistive-pulse measurements on nanofluidic devices with four pores in series to characterize the size distributions of the products in real time...
January 7, 2019: ACS Infectious Diseases
David Bartee, Sara Sanders, Paul D Phillips, Mackenzie J Harrison, Andrew T Koppisch, Caren L Freel Meyers
To fight the growing threat of antibiotic resistance, new antibiotics are required that target essential bacterial processes other than protein, DNA/RNA, and cell wall synthesis which constitute the majority of currently used antibiotics. 1-Deoxy-D-xylulose-5-phosphate (DXP) synthase is a vital enzyme in bacterial central metabolism feeding into the de novo synthesis of thiamine diphosphate (ThDP), pyridoxal phosphate (PLP), and essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate...
January 7, 2019: ACS Infectious Diseases
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