ACS Infectious Diseases

No abstract text is available yet for this article.

The nonproton pumping type II NADH dehydrogenase in Mycobacterium tuberculosis is essential for meeting the energy needs in terms of ATP under normal aerobic and stressful hypoxic environmental states. Type II NADH dehydrogenase conduits electrons into the electron transport chain in Mycobacterium tuberculosis , which results in ATP synthesis. Therefore, the inhibition of NDH-2 ensures the abolishment of the entire ATP synthesis machinery. Also, type II NADH dehydrogenase is absent in the mammalian genome, thus making it a potential target for antituberculosis drug discovery...

Cholesterol is a key carbon source for Mycobacterium tuberculosis (Mtb) survival and persistence within macrophages. However, little is known about the role of cholesterol metabolism by Mtb in host-Mtb interplay. Here, we report the immune suppression mediated by Mtb's cholesterol metabolites. Conducting the cholesterol metabolic profiling and loss-of-function experiments, we show that the cholesterol oxidation products catalyzed by a thiolase FadA5 from Mtb H37Ra, 4-androstenedione (AD), and its derivant 1,4-androstenedione (ADD) inhibit the expression of pro-inflammatory cytokines and thus promote bacterial survival in bone marrow-derived macrophages (BMDMs)...

Since Chagas disease, melioidosis, and Legionnaires' disease are all potentially life-threatening infections, there is an urgent need for new treatment strategies. All causative agents, Trypanosoma cruzi , Burkholderia pseudomallei , and Legionella pneumophila , express a virulence factor, the macrophage infectivity potentiator (MIP) protein, emerging as a promising new therapeutic target. Inhibition of MIP proteins having a peptidyl-prolyl isomerase activity leads to reduced viability, proliferation, and cell invasion...

Tularemia is a deadly disease caused by Francisella tularensis , an emerging intracellular bacterial pathogen that can be disseminated rapidly through aerosols and vector-borne transmission. Recent surveillance data demonstrate an increasing incidence in several countries. Although clinical isolates of Francisella strains are sensitive to currently used antibiotics, engineered or horizontal acquisition of antibiotic resistance is a constant threat to public health. Therefore, the identification of antibiotics that target previously undrugged pathways is required to safeguard human health...

Currently, primaquine is the only malaria transmission-blocking drug recommended by the WHO. Recent efforts have highlighted the importance of discovering new agents that regulate malarial transmission, with particular interest in agents that can be administered in a single low dose, ideally with a discrete and Plasmodium -selective mechanism of action. Here, our team demonstrates an approach to identify malaria transmission-blocking agents through a combination of in vitro screening and in vivo analyses. Using a panel of natural products, our approach identified potent transmission blockers, as illustrated by the discovery of the transmission-blocking efficacy of brusatol...

New drugs and mechanisms of action targeting Mycobacterium tuberculosis are urgently needed to solve the global pandemic of tuberculosis. We previously demonstrated that the 8-hydroxyquinoline series has rapid bactericidal activity against M. tuberculosis . In this work, we determined that the activity of the 8HQ series is potentiated by copper ions and that the activity is dependent on copper since activity was reduced when copper was depleted from the medium. We determined that exposure to 8HQs led to an increase in intracellular copper...

The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii , which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodium such as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P...

Tuberculosis is the leading cause of mortality by infectious agents worldwide. The necrotic debris, known as caseum, which accumulates in the center of pulmonary lesions and cavities is home to nonreplicating drug-tolerant Mycobacterium tuberculosis that presents a significant hurdle to achieving a fast and durable cure. Fluoroquinolones such as moxifloxacin are highly effective at killing this nonreplicating persistent bacterial population and boosting TB lesion sterilization. Fluoroquinolones target bacterial DNA gyrase, which catalyzes the negative supercoiling of DNA and relaxes supercoils ahead of replication forks...

Lipophosphoglycan (LPG) is an important Leishmania virulence factor. It is the most abundant surface glycoconjugate in promastigotes, playing an important role in the interaction with phagocytic cells. While LPG is known to modulate the macrophage immune response during infection, the activation mechanisms triggered by this glycoconjugate have not been fully elucidated. This work investigated the role that LPGs purified from two strains of Leishmania major (FV1 and LV39) play in macrophage activation, considering the differences in their biochemical structures...

Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies...

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe complications that can occur in infections caused by any Plasmodium species. Due to the high lethality rate and the lack of specific treatment for ALI/ARDS, studies aimed at understanding and searching for treatment strategies for such complications have been fundamental. Here, we investigated the protective role of dietary supplementation with DHA-rich fish oil against lung damage induced by Plasmodium berghei ANKA in a murine model...

Here we used native mass spectrometry (native MS) to probe a SARS-CoV protease, PLpro, which plays critical roles in coronavirus disease by affecting viral protein production and antagonizing host antiviral responses. Ultraviolet photodissociation (UVPD) and variable temperature electrospray ionization (vT ESI) were used to localize binding sites of PLpro inhibitors and revealed the stabilizing effects of inhibitors on protein tertiary structure. We compared PLpro from SARS-CoV-1 and SARS-CoV-2 in terms of inhibitor and ISG15 interactions to discern possible differences in protease function...

Vector control of mosquitoes with insecticides is an important tool for preventing the spread of mosquito-borne diseases including malaria, dengue, chikungunya, and Zika. Development of active ingredients for insecticides are urgently needed because existing agents exhibit off-target toxicity and are subject to increasing resistance. We therefore seek to develop noncovalent inhibitors of the validated insecticidal target acetylcholinesterase 1 (AChE1) from mosquitoes. Here we use molecular dynamics simulations to identify structural properties essential for the potency of reversible inhibitors targeting AChE1 from Anopheles gambiae ( Ag AChE1), the malaria-transmitting mosquito, and for selectivity relative to the vertebrate Mus musculus AChE ( m AChE)...

Fungal keratitis (FK) is a blinding corneal infectious disease. The prognosis is frequently unfavorable due to fungal invasion and an excessive host inflammatory response. Licochalcone A (Lico A) exhibits a broad spectrum of pharmacological activities, encompassing antifungal, anti-inflammatory, antioxidation, and antitumor properties. However, the role of Lico A has not yet been studied in FK. In this study, we discovered that Lico A could disrupt Aspergillus fumigatus ( A. fumigatus ) biofilms, inhibit fungal growth and adhesion to host cells, induce alterations of hyphal morphology, and impair the cell membrane and cell wall integrity and mitochondrial structure of A...

Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes...

Klebsiella pneumoniae is consistently ranked among the most problematic multidrug-resistant bacterial pathogens in healthcare systems. Developing novel treatments requires a better understanding of its interaction with the host environment. Although bacteria can synthesize fatty acids, emerging findings suggest a potential preference for their acquisition from the host. Fatty acid profiling of mice revealed a dramatic increase in the level of hepatic lipids during K . pneumoniae infection. The K . pneumoniae fatty acid composition and uptake capabilities were found to be largely clonally conserved...

Acinetobacter baumannii ( A. baumannii ) challenges clinical infection treatment due to its resistance to various antibiotics. Multiple resistance genes in the core genome or mobile elements contribute to multidrug resistance in A. baumannii . Macrolide phosphotransferase gene mphE has been identified in A. baumannii , which is particularly relevant to macrolide antibiotics. Here, we determined the structure of MphE protein in three states: the apo state, the complex state with erythromycin and guanosine triphosphate (GTP), and the complex state with azithromycin and guanosine...

In impoverished nations, the COVID-19 pandemic has led to a widespread occurrence of deadly fungal diseases like mucormycosis. The limited availability of effective antifungal treatments and the emergence of drug-resistant fungal strains further exacerbate the situation. Factors such as systemic steroid use, intravenous drug misuse, and overutilization of broad-spectrum antimicrobials contribute to the prevalence of hospital-acquired infections caused by drug-resistant fungi. Fungal infections exploit compromised immune status and employ intricate mechanisms to evade immune surveillance...

Mycobacterium tuberculosis has evolved a highly specialized system to snatch essential nutrients from its host, among which host-derived cholesterol has been established as one main carbon source for M. tuberculosis to survive within granulomas. The uptake, catabolism, and utilization of cholesterol are important for M. tuberculosis to sustain within the host largely via remodeling of the bacterial cell walls. However, the regulatory mechanism of cholesterol uptake and its impact on bacterium fate within infected hosts remain elusive...