ACS Infectious Diseases

Wed, 06/02/2021 - 04:04
The increase in the prevalence of multidrug-resistant (MDR) Staphylococcus aureus with strong biofilm-forming capacity poses a serious public health concern. Endolysins derived from bacteriophages are a promising solution for antibiotic resistance problems. However, some natural staphylococcal endolysins have several shortcomings, such as low solubility and high sequence homology among domains....
Fri, 05/28/2021 - 04:02
Despite the arguable success of the standardized tuberculosis (TB) treatment regime, a significant number of patients still present with treatment failure. To improve on current TB treatment strategies, we sought to gain a better understanding of the hosts’ response to TB therapy. A targeted metabolomics approach was used to compare the urinary acylcarnitine and amino acid profiles of eventually...
Mon, 05/24/2021 - 04:03
Biofilm formation and hemolysis induced by Staphylococcus aureus are closely related to pathogenicity. However, no drugs exist to inhibit biofilm formation or hemolysis induced by S. aureus in clinical practice. This study found diclazuril had antibacterial action against S. aureus with minimum inhibitory concentrations (MICs) at 50 μM for both methicillin-sensitive S. aureus (MSSA) and...
Sun, 05/02/2021 - 04:02
Developing effective therapeutics or preventive interventions for important health threats is greatly enhanced whenever accessible models can enable the assessment of clinically important outcomes. While no non-human model is ever perfect, inexpensive in vivo small animal models in such as mice are often of great help in assessing the relevant efficacy of potential interventions. In addition to...
Thu, 04/29/2021 - 11:44
Class D β-lactamases have risen to notoriety due to their wide spread in bacterial pathogens, propensity to inactivate clinically important β-lactam antibiotics, and ability to withstand inhibition by the majority of classical β-lactamase inhibitors. Understanding the catalytic mechanism of these enzymes is thus vitally important for the development of novel antibiotics and inhibitors active...
Mon, 04/26/2021 - 04:02
Microbes support their growth in vertebrate hosts by exploiting a large variety of dietary components as nutrients, which determines the composition of gut microbiota. A pathogen Salmonella expands by utilizing 1,2-propanediol, a microbiota-fermented product, during mucosal inflammation. However, it remains largely unknown how the pathogen decides which nutrient to consume from the complex...
Thu, 04/15/2021 - 04:02
Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high...
Tue, 04/13/2021 - 04:02
Vibrio cholerae is the causative agent of cholera, a diarrheal disease that kills tens of thousands of people each year. Cholera is transmitted primarily by the ingestion of drinking water contaminated with fecal matter, and a safe water supply remains out of reach in many areas of the world. In this Review, we discuss host and environmental factors that impact the susceptibility to V. cholerae...
Sat, 04/10/2021 - 04:02
Increasing multidrug resistance in Neisseria gonorrheae is a growing public health crisis. Resistance to the last line therapies, cephalosporins and azithromycin, are of particular concern, fueling the need to discover new treatments. Here, we identified the phosphoglycolipid moenomycin from a screen of microbial natural products against drug-resistant N. gonorrheae as a potent antigonococcal...
Thu, 03/25/2021 - 04:02
Acute diarrheal illness and gastroenteritis caused by Campylobacter jejuni infection remain significant public health risks in developing countries with substantial mortality and morbidity in humans, particularly in children under the age of five. Genetic diversities among Campylobacter jejuni and limited understanding of immunological correlations of host protection remain primary impediments...
Sun, 03/21/2021 - 04:02
Bacterial infections are a major threat to human health, exacerbated by increasing antibiotic resistance. These infections can result in tremendous morbidity and mortality, emphasizing the need to identify and treat pathogenic bacteria quickly and effectively. Recent developments in detection methods have focused on electrochemical, optical, and mass-based biosensors. Advances in these systems...
Sat, 03/20/2021 - 04:02
As the predominant antibody type in mucosal secretions, human colostrum, and breast milk, secretory IgA (SIgA) plays a central role in safeguarding the intestinal epithelium of newborns from invasive enteric pathogens like the Gram-negative bacterium Salmonella enterica serovar Typhimurium (STm). SIgA is a complex molecule, consisting of an assemblage of two or more IgA monomers, joining (J)-...
Thu, 03/18/2021 - 04:02
Burkholderia cepacia complex (Bcc) poses a serious health threat to people with cystic fibrosis or compromised immune systems. Infections often arise from Bcc strains, which are highly resistant to many classes of antibiotics, including β-lactams. β-Lactam resistance in Bcc is conferred largely via PenA-like β-lactamases. Avibactam was previously shown to be a potent inactivator of PenA1. Here,...
Fri, 03/12/2021 - 04:02
Enteric infection with Shigella spp. can lead to symptoms ranging from acute watery diarrhea to sudden, severe dysentery. Approximately 212 000 diarrheal deaths annually are attributed to Shigella with a disproportionate impact in low-resource countries. The impact in under-resourced countries was illustrated by a reanalysis of the Global Enteric Multicenter Study which found that Shigella was...
Fri, 03/12/2021 - 04:02
The pathogen Salmonella enterica is a leading cause of infection worldwide. Nontyphoidal Salmonella (NTS) serovars typically cause inflammatory diarrhea in healthy individuals, and can cause bacteremia in immunocompromised patients, children, and the elderly. Management of NTS infection poses a challenge because antibiotic treatment prolongs fecal shedding of the pathogen and is thus not...
Tue, 03/09/2021 - 04:02
The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual...
Fri, 03/05/2021 - 04:02
Antibiotic resistance nowadays is spreading much faster than the introduction of new antibiotics into clinical practice. There is an urgent need for potential compounds to combat multidrug-resistant (MDR) bacteria. Marine fungi provide a promising source for chemical diversity with antibiotic-like molecules. To identify structurally distinct compounds that effectively eradicate MDR pathogens and...
Thu, 02/18/2021 - 04:02
Effective strategies are needed to deal with invasive fungal infections caused by drug-resistant fungi. Previously, we designed a series of antifungal benzocyclane derivatives based on the drug repurposing of haloperidol. Herein, further structural optimization and antifungal mechanism studies were performed, leading to the discovery of new piperidol derivative B2 with improved synergistic...
Sat, 02/13/2021 - 04:02
Two proteases produced by the SARS-CoV-2 virus, the main protease and papain-like protease, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro and PLpro proteases. These...
Fri, 02/05/2021 - 04:02
Giardiasis is a neglected parasitic diarrheal disease that is particularly associated with poverty. Current treatment options are limited in the face of growing resistance, but the reduced kinome of Giardia lamblia increases the likelihood of identifying nonredundant essential kinases as potential drug targets. Repurposing known and newly identified kinase inhibitors in drug development programs...
Thu, 02/04/2021 - 04:02
Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting human populations, yet CL remains largely ignored in drug discovery programs. CL causes disfiguring skin lesions and often relapses after “clinical cure” using existing therapeutics. To expand the pool of anti-CL lead candidates, we implemented an integrated screening platform comprising three progressive Leishmania...
Tue, 02/02/2021 - 04:02
Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (...
Sun, 01/31/2021 - 04:02
Antibacterial adjuvants are of great significance, since they allow the therapeutic dose of conventional antibiotics to be lowered and reduce the insurgence of antibiotic resistance. Herein, we report that an O-acetylserine sulfhydrylase (OASS) inhibitor can be used as a colistin adjuvant to treat infections caused by Gram-positive and Gram-negative pathogens. A compound that binds OASS with a nM...
Thu, 01/28/2021 - 04:02
Bacterial coinfection in COVID-19 patients has the potential to complicate treatments and accelerate the development of antibiotic resistance in the clinic due to the widespread use of broad-spectrum antibiotics, including in Indonesia. The surge of COVID-19 patients may worsen antibiotic overuse; therefore, information on the actual extent of bacterial coinfection in COVID-19 patients in...
Fri, 01/22/2021 - 04:02
The successful treatment of Helicobacter pylori infections is becoming increasingly difficult due to the rise of resistance against current broad spectrum triple therapy regimens. In the search for narrow-spectrum agents against H. pylori, a high-throughput screen identified two structurally related thienopyrimidine compounds that selectively inhibited H. pylori over commensal members of the gut...
Thu, 01/21/2021 - 04:02
In addition to providing maximal nutritional value for neonatal growth and development, human milk functions as an early defense mechanism against invading pathogens. Human milk oligosaccharides (HMOs), which are abundant in human milk, are a diverse group of heterogeneous carbohydrates with wide ranging protective effects. In addition to promoting the colonization of beneficial intestinal flora...
Thu, 01/14/2021 - 04:01
Pyrazolo[1,5-a]pyrimidin-7(4H)-one was identified through high-throughput whole-cell screening as a potential antituberculosis lead. The core of this scaffold has been identified several times previously and has been associated with various modes of action against Mycobacterium tuberculosis (Mtb). We explored this scaffold through the synthesis of a focused library of analogues and identified key...
Fri, 12/25/2020 - 04:02
Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved...
Sun, 12/13/2020 - 04:01
Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni, a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior...
Thu, 12/10/2020 - 04:02
The development of antimicrobial compounds is now regarded as an urgent problem. Antimicrobial peptides (AMPs) have great potential to become novel antimicrobial drugs. Feleucin-K3 is an α-helical cationic AMP isolated from the skin secretion of the Asian bombinid toad species Bombina orientalis and has antimicrobial activity. In our previous studies, amino acid scanning of Feleucin-K3 was...
Fri, 12/04/2020 - 04:02
Staphylococcus aureus is a common cause of invasive and life-threatening infections that are often multidrug resistant. To develop novel treatment approaches, a detailed understanding of the complex host–pathogen interactions during infection is essential. This is particularly true for the molecular processes that govern the formation of tissue abscesses, as these heterogeneous structures are...
Wed, 12/02/2020 - 04:02
Bacteria utilize versatile strategies to propagate infections within human cells, e.g., by the injection of effector proteins, which alter crucial signaling pathways. One class of such virulence-associated proteins is involved in the AMPylation of eukaryotic Rho GTPases with devastating effects on viability. In order to get an inventory of AMPylated proteins, several technologies have been...
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...

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