Antimicrobial Agents and Chemotherapy

The Research Publications track research that is published across national and international peer-reviewed journals. The most recent articles are available ahead of print and searchable by Journal Title, Subject, USDA Grant Funding Agencies or FDA Grant Funding Agencies. The research publications are tracked across five subject areas: Bacterial Pathogens, Chemical Contaminants, Natural Toxins, Parasites, and Viruses.

Tue, 01/28/2020 - 03:26
The most common mechanism of resistance to β-lactams antibiotics in Gram-negative bacteria is production of β-lactamase enzymes capable of cleaving the β-lactam ring. Inhibition of β-lactamase activity with small-molecule drugs is a proven strategy to restore the potency of many β-lactam antibiotics. Vaborbactam (formerly RPX7009) is a cyclic boronic acid β-lactamase...
Tue, 01/28/2020 - 03:26
We identified fosA3 at a rate of 2.6% in 310 Salmonella isolates from food animals in Guangdong province, China. The fosA3 gene was genetically linked to diverse antibiotic resistance genes (ARGs), including mcr-1, blaCTX-M-14/55, oqxAB, and rmtB. These gene combinations were embedded in heterogeneous fosA3-containing multidrug resistance regions on the transferable ST3-IncHI2 and F33:A–:B...
Tue, 01/28/2020 - 03:26
The worldwide spread of multidrug-resistant Enterobacterales is a serious threat to public health. Here, we compared the MICs of plazomicin, amikacin, gentamicin, and tobramycin against 303 multinational multidrug-resistant Gram-negative bacilli. We followed Clinical and Laboratory Standards Institute (CLSI) guidelines and applied CLSI breakpoints as well as those of the European Committee on...
Tue, 01/28/2020 - 03:26
Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects...
Tue, 01/28/2020 - 03:26
In this study, we aimed to assess the in vitro susceptibility to GSK656 among multiple mycobacterial species and to investigate the correlation between leucyl-tRNA synthetase (LeuRS) sequence variations and in vitro susceptibility to GSK656 among mycobacterial species. A total of 187 mycobacterial isolates, comprising 105 Mycobacterium tuberculosis isolates and 82 nontuberculous mycobacteria (NTM...
Tue, 01/28/2020 - 03:26
Multidrug-resistant Enterobacteriaceae (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels. Here, we...
Sat, 12/21/2019 - 03:40
Community-onset bloodstream infections (CO-BSI) are major causes of severe febrile illness and death worldwide. In light of new data and the growing problem of antimicrobial resistance (AMR) among pathogens causing BSI, we undertook a systematic review of hospital-based studies of CO-BSI among patients hospitalized with fever. Without restriction to language or country, we searched PubMed, Web of...
Sat, 12/21/2019 - 03:40
The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental...
Sat, 12/21/2019 - 03:40
It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides (ADEPs) are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including...
Sat, 12/21/2019 - 03:40
The prevalence of multidrug-resistant Pseudomonas aeruginosa has led to the reexamination of older "forgotten" drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-α-methoxy analogue of ticarcillin, a carboxypenicillin with well-characterized antipseudomonal properties. The α-methoxy modification confers resistance to serine β-lactamases...
Sat, 12/21/2019 - 03:40
Identification of the nucleotide sequences encoding antibiotic resistance elements and determination of their association with antibiotic resistance are critical to improve surveillance and monitor trends in antibiotic resistance. Current methods to study antibiotic resistance in various environments rely on extensive deep sequencing or laborious culturing of fastidious organisms, both of which...
Sat, 12/21/2019 - 03:40
Manogepix (MGX) targets the conserved fungal Gwt1 enzyme required for acylation of inositol early in the glycosylphosphatidylinositol biosynthesis pathway. The prodrug fosmanogepix is currently in clinical development for the treatment of invasive fungal infections. We determined that the median frequencies of spontaneous mutations conferring reduced susceptibility to MGX in Candida albicans, C....
Sat, 12/21/2019 - 03:40
The antifungal susceptibility tests used in clinical laboratories have several limitations. We developed a new test, SensiFONG, based on the detection of chitin levels after exposure to antifungal drugs. The optimal culture conditions were 30°C for 6 h for yeast strains and 26°C for 16 h for molds. The strains were exposed to a range of echinocandin or azole concentrations. Chitin was...
Sat, 12/21/2019 - 03:40
Cfr is a radical S-adenosyl-l-methionine (SAM) enzyme that confers cross-resistance to antibiotics targeting the 23S rRNA through hypermethylation of nucleotide A2503. Three cfr-like genes implicated in antibiotic resistance have been described, two of which, cfr(B) and cfr(C), have been sporadically detected in Clostridium difficile. However, the methylase activity of Cfr(C) has not been...
Sat, 12/21/2019 - 03:40
Understanding the mechanism(s) underpinning drug resistance could lead to novel treatments to reverse the increased tolerance of a pathogen. In this study, paromomycin (PMM) resistance (PMMr) was induced in three Nepalese clinical strains of Leishmania donovani with different inherent susceptibilities to antimony (Sb) drugs by stepwise exposure of promastigotes to PMM. Exposure to PMM resulted in...
Fri, 11/22/2019 - 03:25
Accurate and rapid assessment of Candida auris antifungal drug resistance is crucial for effective infection prevention and control actions, as well as for patient management. Here, performance of a molecular diagnostic platform, enabling rapid identification of FKS1 and ERG11 mutations conferring echinocandin and azole resistance, respectively, was evaluated on a panel of clinical skin swabs....
Fri, 11/22/2019 - 03:25
Salmonella enterica is a natural bacterial pathogen of humans and animals that causes systemic infection or gastroenteritis. During systemic infection, Salmonella generally resides within professional phagocytes, typically macrophages, whereas gastroenteritis is caused by infection of epithelial cells. We are only beginning to understand which host pathways contribute to Salmonella survival in...
Fri, 11/22/2019 - 03:25
In Enterobacteriaceae, quinolone resistance is largely attributed to mutations in the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC, and parE and plasmid-mediated quinolone resistance (PMQR) genes [e.g., qnr genes, aac(6′)-Ib-cr, or qepA]. The functionality of four qepA genes, designated qepA1 to qepA4, has been described in the literature (1–5); however, other qepA genes...
Fri, 11/22/2019 - 03:25
qnr genes are found in aquatic bacteria and were present in the bacterial community before the introduction of synthetic quinolones. Their natural functions are unknown. We evaluated expression of chromosomal qnr in Vibrio species in response to environmental stresses and DNA-damaging agents. Subinhibitory concentrations of quinolones, but not other DNA-damaging agents, increased expression of...
Fri, 11/22/2019 - 03:25
Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the first-in-human study, single ascending oral doses of nafithromycin (100 to 1,200 mg) were administered to subjects under fasted or fed conditions, with effects of food on bioavailability of nafithromycin studied at the dose...
Fri, 11/22/2019 - 03:25
Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A to G), which differ by 35% to 68% in amino acid sequences, necessitates the development of serotype-specific countermeasures. We present results of a phase 1 clinical study of...
Fri, 11/22/2019 - 03:25
Worldwide, tuberculosis (TB) is the leading cause of death due to infection with a single pathogenic agent, Mycobacterium tuberculosis. In the absence of an effective vaccine, new, more powerful antibiotics are required to halt the growing spread of multidrug-resistant strains and to shorten the duration of TB treatment. However, assessing drug efficacy at the preclinical stage remains a long and...
Fri, 11/22/2019 - 03:25
Multidrug efflux pumps play an important role in antibiotic resistance in bacteria. In Pseudomonas aeruginosa, the MexXY pump provides intrinsic resistance to many antimicrobials, including aminoglycosides. The expression of the mexXY operon is negatively regulated by the MexZ repressor. This repression is alleviated in response to antibiotic-induced ribosome stress, which results in increased...
Fri, 11/22/2019 - 03:25
A large OXA-48 outbreak in The Netherlands involved the spread of OXA-48-producing Enterobacteriaceae among at least 118 patients, suggesting horizontal transfer of this resistance gene through one or more plasmids. Elucidating transmission dynamics of resistance plasmids is hampered by the low resolution of classic typing methods. This study aimed to investigate the molecular epidemiology of...
Fri, 11/22/2019 - 03:25
Spores are required for long-term survival of many organisms, including most fungi. For the majority of fatal human fungal pathogens, spore germination is the key process required to initiate vegetative growth and ultimately cause disease. Because germination is required for pathogenesis, the process could hold fungus-specific targets for new antifungal drug development. Compounds that inhibit...
Fri, 11/22/2019 - 03:25
Antimalarial drug resistance is a substantial impediment to malaria control. The spread of resistance has been described using genetic markers, which are important epidemiological tools. We carried out a temporal analysis of changes in allele frequencies of 12 drug resistance markers over 2 decades of changing antimalarial drug policy in Kenya. We did not detect any of the validated kelch 13 (k13...
Fri, 11/22/2019 - 03:25
Valganciclovir, the ganciclovir prodrug, is an antiviral agent administered orally to prevent or treat cytomegalovirus infection in solid-organ transplant recipients. The valganciclovir dosing regimen in children is still controversial, as the number of patients reaching the area under the concentration-time curve at steady state (AUCss) target (40 to 60 mg·h/liter) remains highly variable...
Fri, 11/22/2019 - 03:25
Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially available vaccine that is sufficiently effective at preventing the acquisition of pulmonary tuberculosis in adults. In this study, preexposure prophylactic pulmonary delivery of active aerosolized antituberculosis bacteriophage D29 was evaluated as an option...
Wed, 10/23/2019 - 03:34
ACC-1 is a plasmid-encoded class C β-lactamase identified in clinical isolates of Klebsiella pneumoniae, Proteus mirabilis, Salmonella enterica, and Escherichia coli. ACC-1-producing bacteria are susceptible to cefoxitin, whereas they are resistant to oxyimino cephalosporins. Here, we depict crystal structures of apo ACC-1, adenylylated ACC-1, and acylated ACC-1 complexed with cefotaxime and...
Wed, 10/23/2019 - 03:34
Horizontal transfer of plasmids encoding antimicrobial resistance and virulence determinants has been instrumental in Staphylococcus aureus evolution, including the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA). In the early 1990s, the first CA-MRSA strain isolated in Western Australia (WA), WA-5, encoded cadmium, tetracycline, and penicillin resistance genes on...
Wed, 10/23/2019 - 03:34
Multidrug-resistant tuberculosis (TB) is an alarming threat, and targeted deep sequencing (DS) may be an effective method for rapid identification of drug-resistant profiles, including detection of heteroresistance. We evaluated the sensitivity and specificity of targeted DS versus phenotypic drug susceptibility testing (pDST) among patients starting first-line anti-TB therapy in Botswana....
Wed, 10/23/2019 - 03:34
New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas...
Wed, 10/23/2019 - 03:34
Antimicrobial resistance (AMR) is a major public health problem that requires publicly available tools for rapid analysis. To identify AMR genes in whole-genome sequences, the National Center for Biotechnology Information (NCBI) has produced AMRFinder, a tool that identifies AMR genes using a high-quality curated AMR gene reference database. The Bacterial Antimicrobial Resistance Reference Gene...
Tue, 09/24/2019 - 03:27
Carbapenem-hydrolyzing class D carbapenemases (CHDLs) are enzymes that produce resistance to the last-resort carbapenem antibiotics, severely compromising the available therapeutic options for the treatment of life-threatening infections. A broad variety of CHDLs, including OXA-23, OXA-24/40, and OXA-58, circulate in Acinetobacter baumannii, while the OXA-48 CHDL is predominant in...
Tue, 09/24/2019 - 03:27
Selection of extended-spectrum mutations in narrow-spectrum oxacillinases (e.g., OXA-2 and OXA-10) is an emerging mechanism for development of in vivo resistance to ceftolozane-tazobactam and ceftazidime-avibactam in Pseudomonas aeruginosa. Detection of these challenging enzymes therefore seems essential to prevent clinical failure, but the complex phenotypic plasticity exhibited by this species...
Tue, 09/24/2019 - 03:27
Salmonella enterica serovar Goldcoast infection was rare in Taiwan; it was not detected in routine surveillance from 2004 to 2013. This serovar was first identified in 2014, but the frequency of infection remained low until 2017. From 2014 to 2016, all but one isolate was pan-susceptible. S. Goldcoast infections abruptly increased in 2018, and all isolates were multidrug-resistant (MDR). All MDR...
Tue, 09/24/2019 - 03:27
Glutamate amidation, a secondary modification of the peptidoglycan, was first identified in Staphylococcus aureus. It is catalyzed by the protein products of the murT and gatD genes, which are conserved and colocalized in the genomes of most sequenced Gram-positive bacterial species. The MurT-GatD complex is required for cell viability, full resistance to β-lactam antibiotics, and resistance...
Tue, 09/24/2019 - 03:27
A pan-susceptible Salmonella enterica serovar Worthington isolate was detected in the stool of a man returning from Sri Lanka. Under ceftriaxone treatment, a third-generation cephalosporin (3GC)-resistant Salmonella Worthington was isolated after 8 days. Molecular analyses indicated that the two isolates were identical. However, the latter strain acquired a blaDHA-1-carrying IncFII plasmid...
Tue, 09/24/2019 - 03:27
Carbapenem-resistant Enterobacteriaceae (CRE) can be mechanistically classified into carbapenemase-producing Enterobacteriaceae (CPE) and non-carbapenemase-producing carbapenem nonsusceptible Enterobacteriaceae (NCPCRE). We sought to investigate the effect of antecedent carbapenem exposure as a risk factor for NCPCRE versus CPE. Among all patients with CRE colonization and infection, we conducted...
Tue, 09/24/2019 - 03:27
Oral candidiasis (OC) caused by the fungal pathogen Candida albicans is the most common opportunistic infection in immunocompromised populations. The dramatic increase in resistance to common antifungal agents has emphasized the importance of identifying alternative therapeutic options. Antimicrobial peptides have emerged as promising drug candidates due to their antimicrobial properties;...
Tue, 09/24/2019 - 03:27
The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel...
Mon, 09/23/2019 - 03:22
Salmonella genomic island 3 (SGI3) was first described as a chromosomal island in Salmonella 4,[5],12:i:–, a monophasic variant of Salmonella enterica subsp. enterica serovar Typhimurium. The SGI3 DNA sequence detected from Salmonella 4,[5],12:i:– isolated in Japan was identical to that of a previously reported one across entire length of 81 kb. SGI3 consists of 86 open reading frames...
Mon, 09/23/2019 - 03:22
Nontuberculous mycobacteria (NTM) are highly drug-resistant, opportunistic pathogens that can cause pulmonary disease. The outcomes of the currently recommended treatment regimens are poor, especially for Mycobacterium abscessus. New or repurposed drugs are direly needed. Auranofin, a gold-based antirheumatic agent, was investigated for Mycobacterium tuberculosis. Here, we test auranofin against...
Mon, 09/23/2019 - 03:22
In the quest for new antibacterial lead structures, activity screening against Mycobacterium tuberculosis identified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoe Loranthus micranthus. Structure-activity relationship studies indicated that 3-O-methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms showed the strongest growth...
Sun, 09/22/2019 - 03:22
The gene mcr-1 conferring resistance to last-line antibiotic colistin has been reported globally. Here, we describe the first detection of plasmid-mediated colistin resistance in Russian wildlife, an isolate of Escherichia coli sequence type 2280 from a black kite (Milvus migrans) scavenging raptor. Whole-genome sequencing and plasmid transferability experiments revealed that mcr-1.1 was located...
Sun, 09/22/2019 - 03:22
We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and...
Sun, 09/22/2019 - 03:22
Antibiotic tolerance, the ability to temporarily sustain viability in the presence of bactericidal antibiotics, constitutes an understudied and yet potentially widespread cause of antibiotic treatment failure. We have previously shown that the Gram-negative pathogen Vibrio cholerae can tolerate exposure to the typically bactericidal β-lactam antibiotics by assuming a spherical morphotype...