ACS Infectious Diseases

Fri, 11/27/2020 - 04:02
Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) has emerged as an enticing new target since its function is conserved and essential for bacterial fitness, and because its inhibition or dysregulation leads to bacterial cell death. ClpP protease function controls global protein homeostasis and is, therefore,...
Thu, 11/26/2020 - 04:01
Staphylococcus aureus is a primary pathogen responsible for causing postoperative infections as it survives and persists in host cells, including osteoblasts and macrophages. These cells then serve as reservoirs resulting in chronic infections. Most traditional antibiotics have poor effects on intracellular S. aureus because they cannot enter the cell. Herein, a cell-penetrating peptide TAT-KR-12...
Mon, 11/16/2020 - 04:02
Bacterial cell surface glycans are quintessential drug targets due to their critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell envelope glycocalyx contains distinctive monosaccharides that are stitched together into higher order glycans to yield exclusively bacterial structures that are critical for strain fitness and pathogenesis. However, the...
Mon, 11/02/2020 - 04:02
With the rising prevalence of multidrug resistance, there is an urgent need to develop novel antibiotics. Many putative antibiotics demonstrate promising in vitro potency but fail in vivo due to poor drug-like qualities (e.g., serum half-life, oral absorption, solubility, and toxicity). These drug-like properties can be modified through the addition of chemical protecting groups, creating “...
Mon, 11/02/2020 - 04:02
Enterohemorrhagic Escherichia coli (EHEC) is the causative agent of severe diarrheal disease in humans. Cattle are the natural reservoir of EHEC, and approximately 75% of EHEC infections in humans stem from bovine products. Many common bacterial pathogens, including EHEC, rely on chemical communication systems, such as quorum sensing (QS), to regulate virulence and facilitate host colonization....
Sun, 11/01/2020 - 04:02
Schistosomiasis is a parasitic disease that affects approximately 200 million people in developing countries. Current treatment relies on just one partially effective drug, and new drugs are needed. Tubulin and microtubules (MTs) are essential constituents of the cytoskeleton in all eukaryotic cells and considered potential drug targets to treat parasitic infections. The α- and β-tubulin of...
Fri, 10/30/2020 - 04:03
Bacterial type II phosphopantetheinyl transferases (PPTases), required for the activation of many cellular mega-synthases, have been validated as promising drug targets in several pathogens. Activation of the blue-pigment-synthesizing nonribosomal peptide synthetase BpsA by a target PPTase can be used to screen in vitro for new antibiotic candidates from chemical libraries. For a complete...
Sat, 10/24/2020 - 04:02
An antivirulence agent against Vibrio vulnificus named quoromycin (QM) was discovered by a phenotype-based elastase inhibitor screening. Using the fluorescence difference in two-dimensional gel electrophoresis (FITGE) approach, SmcR, a quorum-sensing master regulator and homologue of LuxR, was identified as the target protein of QM. We confirmed that the direct binding of QM to SmcR inhibits the...
Mon, 10/12/2020 - 04:01
Strongyloides stercoralis is a soil-transmitted helminth affecting an estimated 30–100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against...
Tue, 10/06/2020 - 04:02
Next-generation treatment strategies to treat osteomyelitis with complete eradication of pathogen at the bone nidus and prevention of emergence of drug resistance is a real challenge in orthopedics. Conventional treatment strategies including long-term adherence of patients to systemic antibiotic delivery, local delivery using nondegradable vehicles, and surgical debridement are not completely...
Mon, 10/05/2020 - 04:02
The emergence and spread of multidrug resistant (MDR) pathogens with acquired resistance to almost all available antimicrobial agents has severely threatened the international healthcare community over the last two decades. The last resort antibiotic vancomycin is critical for treatment of several of these pathogens; howeverc vancomycin resistance is spreading due to the undesired accumulation of...
Sun, 10/04/2020 - 04:02
Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion...
Fri, 09/25/2020 - 04:01
Shigella flexneri targets colonic cells in humans to initiate invasive infection processes that lead to dysentery, and direct interactions between their lipopolysaccharide O antigens and blood group A related glycans are involved in the cell adherence interactions. Here, we show that treatment with Tn and sialyl-Tn glycans, monoclonal antibodies and lectins reactive to Tn/sialyl-Tn, and luteolin...
Mon, 09/21/2020 - 04:01
Resistance to last-resort carbapenem antibiotics is an increasing threat to human health, as it critically limits therapeutic options. Metallo-β-lactamases (MBLs) are the largest family of carbapenemases, enzymes that inactivate these drugs. Among MBLs, New Delhi metallo-β-lactamase 1 (NDM-1) has experienced the fastest and largest worldwide dissemination. This success has been attributed to the...
Sat, 08/29/2020 - 04:02
Infections caused by drug-resistant pathogens are a worldwide challenge for public health. Antimicrobial peptides (AMPs) are regarded as promising antibiotic alternatives for the treatment of drug-resistant infections. In the present study, a series of small peptides were designed based on our previously reported sea snake AMP Hc-CATH. From them, the lead peptide HC1-D2, a truncated peptide...
Sat, 08/22/2020 - 04:01
Colistin is an antibiotic of last resort used to treat infections caused by multidrug-resistant Gram-negative bacterial pathogens. The recent surge in reported cases of colistin-resistant infections urgently calls for fast and reliable diagnostic methods, which can be used for the facile detection and proper treatment of these challenging infections. A major mechanism of colistin resistance...
Fri, 08/21/2020 - 04:02
The clinical effectiveness of the important β-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address this resistance issue, multiple β-lactam/β-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of...
Fri, 08/21/2020 - 04:02
Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs...
Tue, 08/18/2020 - 04:01
Cytotoxic frog antimicrobial peptide Temporin L (TempL) is an attractive molecule for the design of lead antimicrobial agents due to its short size and versatile biological activities. However, noncytotoxic TempL variants with desirable biological activities have rarely been reported. TempL analogue Q3K,TempL is water-soluble and possesses a significant antiendotoxin property along with...
Sat, 08/08/2020 - 04:02
Antimicrobial peptides (AMPs) are promising candidates for new therapeutics to combat the emergence of an increasing number of multidrug-resistant pathogens. However, a major obstacle to the systemic application of AMPs is their possible toxicity. In this study, we improved the therapeutic index of the typical AMP F5W-magainin 2 by simultaneously introducing positive charges (+9–+10) and Pro...
Wed, 07/29/2020 - 04:01
Cholesterol is a major carbon source for Mycobacterium tuberculosis (Mtb) during infection, and cholesterol utilization plays a significant role in persistence and virulence within host macrophages. Elucidating the mechanism by which cholesterol is degraded may permit the identification of new therapeutic targets. Here, we characterized EchA19 (Rv3516), an enoyl-CoA hydratase involved in...
Sat, 07/25/2020 - 04:01
Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better...
Mon, 07/20/2020 - 04:01
Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-d]pyrimidine compound 1 (K-5a2) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the...
Sun, 07/19/2020 - 04:01
The clinical management of bacterial biofilm infections represents an enormous challenge in today’s healthcare setting. The NIH estimates that 65% of bacterial infections are biofilm-related, and therapeutic outcomes are positively correlated with early intervention. Currently, there is no reliable imaging technique to detect biofilm infections in vivo, and current clinical protocols for accurate...
Fri, 07/10/2020 - 04:02
Human African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3′-deoxytubercidin (5), a lead compound with activity against central-nervous-stage human African trypanosomiasis, we investigate the structure–activity...
Fri, 07/10/2020 - 04:02
As one of the main causes of bacterial diarrhea and a major risk factor for triggering Guillain–Barré autoimmune syndrome, campylobacteriosis, that is, Campylobacter spp. infections, represents a major health issue worldwide. There is thus a pressing need for developing an effective and broad-coverage campylobacteriosis vaccine. Campylobacter jejuni, an encapsulated, multidrug resistant Gram-...
Thu, 06/25/2020 - 04:03
Tilimycin is an enterotoxin produced by the opportunistic pathogen Klebsiella oxytoca that causes antibiotic-associated hemorrhagic colitis (AAHC). This pyrrolobenzodiazepine (PBD) natural product is synthesized by a bimodular nonribosomal peptide synthetase (NRPS) pathway composed of three proteins: NpsA, ThdA, and NpsB. We describe the functional and structural characterization of the fully...
Fri, 06/12/2020 - 04:02
Bacterial infections are urgent threats to human health, especially in light of rising rates of antibiotic resistance, and their ubiquity demands the development of efficient diagnostic platforms. Electrochemical biosensors for point-of-care testing are garnering interest due to their speed, sensitivity, and selectivity as well as their inexpensive, user-friendly operation. These biosensors have...
Tue, 06/09/2020 - 04:05
Ricin toxin A subunit (RTA) removes an adenine from the universally conserved sarcin/ricin loop (SRL) on eukaryotic ribosomes, thereby inhibiting protein synthesis. No high affinity and selective small molecule therapeutic antidotes have been reported against ricin toxicity. RTA binds to the ribosomal P stalk to access the SRL. The interaction anchors RTA to the P protein C-termini at a well-...
Mon, 06/08/2020 - 04:02
Chemistry campaigns identified amphiphilic indolyl Mannich bases as novel membrane-permeabilizing antimycobacterials. Spiroketal analogs of this series showed increased potency, and the lead compound 1 displayed efficacy in a mouse model of tuberculosis. Yet the mechanism by which the spiroketal moiety accomplished the potency “jump” remained unknown. Consistent with its membrane-permeabilizing...
Mon, 06/08/2020 - 04:02
Viridicatumtoxins are a rare class of tetracycline-like antibiotics that strongly inhibit drug-resistant Gram-positive bacteria. Although reported to exhibit in vitro inhibition activity to undecaprenyl pyrophosphate synthase (UPPS), an essential enzyme in bacterial cell wall synthesis, the biological targets and mechanism of action of viridicatumtoxins, especially the drug–target interactions,...
Sun, 06/07/2020 - 04:03
Staphylococcus aureus is notoriously known for its rapid development of resistance to conventional antibiotics. S. aureus can alter its membrane composition to reduce the killing effect of antibiotics and antimicrobial peptides (AMPs). To obtain a more complete picture, this study identified the resistance genes of S. aureus in response to human cathelicidin LL-37 peptides by screening the...
Sun, 06/07/2020 - 04:03
Cytochrome bd (cyt-bd) oxygen reductases have a high affinity to oxygen and use the two electrons provided by ubiquinol or menaquinol, like in mycobacteria, to reduce oxygen to water. Although they do not pump protons from the cytoplasmic to the periplasmic side, they generate a proton motive force due to the release of protons after quinol oxidation. Here, we show that the mycobacterial cyt-bd...
Sat, 06/06/2020 - 04:03
Despite a significant decline in morbidity and mortality over the last two decades, in 2018 there were 228 million reported cases of malaria and 405000 malaria-related deaths. Artemisinin, the cornerstone of artemisinin-based combination therapies, is the most potent drug in the antimalarial armamentarium against falciparum malaria. Heme-mediated activation of artemisinin and its derivatives...
Sat, 06/06/2020 - 04:02
Poor patient adherence to antiretroviral medication represents a major obstacle for managing disease and reducing rates of new HIV infections. The measurement of patient drug levels is the most objective method of determining adherence. Tenofovir and tenofovir diphosphate are metabolites of some of the most common HIV medications for treatment and prevention and can be quantified by mass...
Thu, 04/16/2020 - 03:36
Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen Pseudomonas aeruginosa (PA). This activity holds promise in the treatment of multidrug resistant infections found in immunocompromised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR...
Thu, 04/02/2020 - 03:34
The Burkholderia cepacia complex is a group of closely related bacterial species with large genomes that infect immunocompromised individuals and those living with cystic fibrosis. Some of these species are found more frequently and cause more severe disease than others, yet metabolomic differences between these have not been described. Furthermore, our understanding of how these species respond...
Tue, 03/31/2020 - 03:35
The emergence and rapid spread of antibiotic resistance poses a serious threat to healthcare systems across the globe. The existence of carbapenemase-producing Enterobacteriaceae (CPE) such as Klebsiella pneumoniae renders the use of carbapenems, the last-resort class of β-lactam antibiotics, ineffective against bacterial infections, often leading to CPE-associated mortalities. Current methods of...
Mon, 03/30/2020 - 03:33
In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR...
Wed, 03/25/2020 - 03:33
Vibrio cholerae (V. cholerae) uses the autoinducer CAI-1 (cholera autoinducer 1) and several linked quorum sensing systems in order to efficiently sense its ever-changing environment and optimally coordinate population-wide gene expression. Indole has been reported as an important signal that is sensed by V. cholerae, and here, we report the synthesis and evaluation of a focused library of...
Wed, 03/18/2020 - 03:34
Retroviral reverse transcriptases (RTs) have the ability to carry out strand displacement DNA synthesis in the absence of accessory proteins. Although studies with RTs and other DNA polymerases suggest that fingers subdomain residues participate in strand displacement, molecular determinants of this activity are still unknown. A mutant human immunodeficiency virus type 2 (HIV-2) RT (M41L/D67N/...
Sat, 03/14/2020 - 03:33
Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a...
Fri, 03/13/2020 - 03:33
The role of molecular arrangement of hydrophobic and hydrophilic groups for designing membrane-active molecules remains largely ambiguous. To explore this aspect, herein we report a series of membrane-active small molecules by varying the spatial distribution of hydrophobic groups. The two terminal amino groups of linear triamines such as diethylene triamine, bis(trimethylene)triamine, and bis(...
Thu, 03/12/2020 - 03:36
The emergence and prevalence of carbapenem-resistant bacterial infection have seriously threatened the clinical use of almost all β-lactam antibacterials. The development of effective metallo-β-lactamase (MβL) inhibitors to restore the existing antibiotics efficacy is an ideal alternative. Although several types of serine-β-lactamase inhibitors have been successfully developed and used in...
Wed, 03/11/2020 - 03:35
The ability to respire and generate adenosine triphosphate (ATP) is essential for the physiology, persistence, and pathogenicity of Mycobacterium tuberculosis, which causes tuberculosis. By employing a lead repurposing strategy, the malarial cytochrome bc1 inhibitor SCR0911 was tested against mycobacteria. Docking studies were carried out to reveal potential binding and to understand the binding...
Tue, 03/10/2020 - 03:34
The nucleocapsid protein (NC) is a highly conserved protein that plays key roles in HIV-1 replication through its nucleic acid chaperone properties mediated by its two zinc fingers and basic residues. NC is a promising target for antiviral therapy, particularly to control viral strains resistant to currently available drugs. Since calixarenes with antiviral properties have been described, we...
Sun, 03/08/2020 - 04:34
Biofilm inhibition by exogenous molecules has been an attractive strategy for the development of novel therapeutics. We investigated the biofilm inhibitor taurolithocholic acid (TLCA) and its effects on the specialized metabolism, virulence, and biofilm formation of the clinically relevant bacterium Pseudomonas aeruginosa strain PA14. Our study shows that TLCA alters the specialized metabolism,...
Sun, 03/08/2020 - 04:34
Antibiotic resistance is a worldwide threat due to the decreasing supply of new antimicrobials. Novel targets and innovative strategies are urgently needed to generate pathbreaking drug compounds. NAD kinase (NADK) is essential for growth in most bacteria, as it supports critical metabolic pathways. Here, we report the discovery of a new class of antibacterials that targets bacterial NADK. We...
Sun, 03/08/2020 - 04:34
Protein S-palmitoylation is an important post-translational modification (PTM) in blood stages of the malaria parasite, Plasmodium falciparum. S-palmitoylation refers to reversible covalent modification of cysteine residues of proteins by saturated fatty acids. In vivo, palmitoylation is regulated by concerted activities of DHHC palmitoyl acyl transferases (DHHC PATs) and acyl protein...
Sat, 03/07/2020 - 03:33
LpxD, acyl-ACP-dependent N-acyltransferase, is the third enzyme of lipid A biosynthesis in Gram-negative bacteria. A recent probe-based screen identified several compounds, including 6359-0284 (compound 1), that inhibit the enzymatic activity of Escherichia coli (E. coli) LpxD. Here, we use these inhibitors to chemically validate LpxD as an attractive antibacterial target. We first found that...

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