ACS Infectious Diseases最新文献

Malaria caused by Plasmodium falciparum continues to remain a global health challenge. Its prevention, treatment and elimination efforts are threatened by the inevitable emergence of drug resistance to currently effective treatment regimes. New antimalarials with distinct modes of action and multistage and multispecies activity will be an important addition to the arms race against the malarial parasite. P. falciparum’s epigenome represents a promising target in this battle and offers exciting opportunities for targeted intervention. With an unusually AT-rich genome, a relative paucity of specific transcription factors and limited heterochromatin, epigenetic control has emerged as an important contributor to P. falciparum’s survival and virulence. P. falciparum histones are marked dynamically with a vast array of post translational modifications. These include several well studied and some novel marks. The parasite has an epigenetic signature distinct from its host and shows several parasite-specific adaptations. The regulators of these marks remain understudied, however. While histone acetylation and its regulators have been more extensively studied in the field, research on other epigenetic effectors is also catching up. This review highlights the research efforts aimed at understanding the role of the parasite’s histone lysine methyltransferases in shaping transcriptional regulation and the histone modification landscape.

Hantaviruses are zoonotic pathogens that are spread by rodents and can cause severe and fatal disease in humans. “New World” hantaviruses (endemic to North and South America) include the human pathogenic Andes orthohantavirus (ANDV), Choclo orthohantavirus (CHOV), and Sin Nombre orthohantavirus (SNV). Human infections can lead to hantavirus cardiopulmonary syndrome (HCPS), which is associated with ∼40% mortality. Currently, there are no FDA-approved hantavirus vaccines or treatments, but neutralizing antibodies targeting the glycoproteins Gn and Gc have been shown to be protective in animals. Here, we develop nanoparticle immunogens bearing the Gn head domain (Gn^H) from ANDV, CHOV, or SNV. Initial immunization studies with the ANDV-Gn^H monomer indicated that this antigen elicited a reactive but non-neutralizing antibody response in mice. To bolster the immune response, we developed a strategy to link Gn^Hs to mi3 nanoparticles using the SpyCatcher/SpyTag bioconjugation technology. We found that ANDV-Gn^H-mi3 nanoparticles elicited a cross-reactive antibody response that neutralized pseudotyped viruses containing ANDV and CHOV glycoproteins but not SNV. In contrast, CHOV-Gn^H-mi3 nanoparticles elicited only a homotypic neutralizing response. Finally, the reactivity of sera from mice immunized with a cocktail of ANDV-Gn^H-mi3 and SNV-Gn^H-mi3 nanoparticles was similar to sera from mice immunized with ANDV-Gn^H-mi3, only indicating that the SNV-Gn^H-mi3 antibody response was not even homotypically neutralizing. These results suggest that there are differences in immunodominance that may contribute to the breadth of the hantavirus-targeting neutralizing response elicited by Gn^H-based immunogens. Nonetheless, the cross-neutralizing sera obtained by ANDV-Gn^H-mi3 immunization suggest that developing broad immunogens may be possible with appropriate engineering.

Clostridioides difficile infection (CDI) is responsible for the majority of identifiable antibiotic-associated diarrhea. Epidemiological studies have consistently shown that women are more at risk for CDI than men. C. difficile is spread by spores that germinate in the antibiotic-altered gut of patients to generate toxin-producing vegetative cells. Since germination is required for CDI, we have shown that cholan-24-amides containing m-sulfanilic acid (CamSA) or aniline (CaPA) inhibit C. difficile spore germination and prevent CDI in rodents. In this study, we found that CDI prophylaxis showed clear sexual dimorphism. Male mice developed less severe CDI but were also more refractory to treatment. On the other hand, anti-germinants protected female mice from developing CDI during most stages of their estrous cycle. Interestingly, infection sexual dimorphism was reversed in hamsters, with male hamsters developing more severe CDI signs than females. Furthermore, anti-germinant compounds protected female hamsters more strongly than male hamsters.

Toxicity and rising resistance to current leishmaniasis drugs highlight the need for alternative therapies. Manganese porphyrins (MnPs) have demonstrated therapeutic potential in various oxidative stress-based diseases/ailments due to their redox-modulating properties. Thus, this study aimed to evaluate the redox-active effects of MnTE-2-PyP⁵⁺ (BMX-010, AEOL10113, MnP ethyl) combined with ascorbate (Asc, vitamin C) on Leishmania amazonensis, Leishmania braziliensis, and Leishmania chagasi in vitro. The effects on promastigote growth were assessed, and the mechanism of action was studied by quantifying reactive oxygen species (ROS) and using catalase to evaluate H₂O₂ involvement. The effects on intracellular amastigotes and the mitochondrial membrane potential (ΔΨm) of promastigotes from the most susceptible species were evaluated. Cytotoxicity assays were carried out on mammalian cells. MnP ethyl alone had no impact on parasite growth; however, MnP ethyl/Asc treatment led to a significant reduction in the promastigote growth: 88% for L. amazonensis, 43% for L. chagasi, and 37% for L. braziliensis after 48 h. MnP ethyl/Asc generated about 300% more ROS than the untreated control and induced ΔΨm depolarization. Catalase addition restored parasite survival, confirming H₂O₂ as the primary mediator of the MnP ethyl/Asc effect. Moreover, MnP ethyl/Asc exhibited minimal cytotoxicity on mammalian cells. The MnP ethyl/Asc treatment reduced the infection index by about 58% and the number of amastigotes per macrophage by 42% in L. amazonensis after 24 h. These findings demonstrated that MnP ethyl/Asc exerted an antileishmanial effect through oxidative stress, providing a promising alternative for preclinical evaluation.

Cerebral malaria (CM), a fatal neurological complication arising from Plasmodium falciparum (P. falciparum) infection, remains a significant global health challenge due to the inadequacy of current drugs and vaccines. Consequently, novel therapeutic strategies for CM are urgently needed. Recent research identifies platelets as pivotal in CM pathogenesis, significantly contributing to immunopathological damage and vascular blockage. Platelet-derived transforming growth factor (TGF)-β1 induces apoptosis in endothelial cells, fostering microangiopathy and potentially compromising blood–brain barrier integrity, thus provoking brain edema and inflammation. Notably, TGF-β1 concentrations vary markedly between systemic and local levels, with reduced TGF-β1 levels in mouse/human tissue and peripheral circulation correlating with CM severity. The primary regulatory mechanism involves isolated platelets interacting with infected red blood cells and brain endothelium, elevating local TGF-β1 production, and possibly harming brain endothelial cells. Future CM prevention or treatment strategies should focus on targeting TGF-β1, with an emphasis on brain-targeted drug delivery methods. Exosomes, as natural drug carriers, are extensively utilized for brain-specific delivery. Exosomes loaded with TGF-β1 antibodies, which were surface to enhancing brain-targeting ability, offer a promising therapeutic approach for CM.

Gonorrhea, a sexually transmitted infection caused by Neisseria gonorrhoeae, remains a major public health concern. Fluoroquinolones, which target gyrase and topoisomerase IV, once served as first-line therapy for gonorrhea. However, rising target-mediated resistance led to their removal from treatment guidelines. In response to growing antibacterial resistance, gepotidacin, a first-in-class triazaacenaphthylene, offers a promising new treatment strategy. Gepotidacin targets gyrase and topoisomerase IV but is structurally and mechanistically different from fluoroquinolones. A phase III clinical trial of gepotidacin in the treatment of uncomplicated urogenital gonorrhea demonstrated a positive outcome. However, interactions of the drug with N. gonorrhoeae gyrase and topoisomerase IV have not been reported. Consequently, we determined the targeting of gepotidacin in N. gonorrhoeae cells and its effects on purified N. gonorrhoeae gyrase and topoisomerase IV. Although fluoroquinolones primarily target gyrase in Gram-negative bacteria, gepotidacin displayed well-balanced dual-targeting of both gyrase and topoisomerase IV in cultured cells. Reduced gepotidacin susceptibility required concurrent target-specific mutations in both enzymes, predicting a low propensity for developing target-mediated resistance. Consistent with this cellular dual-targeting, gepotidacin inhibited gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed DNA decatenation at similar low micromolar concentrations. Gepotidacin also induced primarily single-stranded DNA breaks mediated by both enzymes at comparable concentrations. Finally, mutations in aspartic acid residues predicted to mediate important gepotidacin-protein interactions in N. gonorrhoeae gyrase (GyrA^D90) and topoisomerase IV (ParC^D86) markedly diminished the activity of gepotidacin against the respective enzymes. Our findings differentiate gepotidacin targeting and mechanism from those of fluoroquinolones and highlight its potential to combat drug-resistant gonorrhea.

Schistosomiasis, a neglected tropical disease caused by trematodes of Schistosoma genus, urgently requires new treatments due to praziquantel’s limited efficacy against juvenile worms as well as the threat of drug resistance. In this study, we evaluated a series of benzodeazaoxaflavin (BDF4)-based compounds as inhibitors of the parasite’s epigenetic enzyme SmSirt2. Three compounds, 7–9 (MC2346, MC2141, and MC2345), showed activity against both Liberian and Puerto Rican strains of Schistosoma mansoni. The compounds reduced schistosomula and adult worm pair viability, pairing, and egg production, with low cytotoxicity in mammalian cells. These effects were linked to histone H3 hyperacetylation and cytochrome c-mediated apoptosis, confirming SmSirt2 as a functional target. These findings support the development of SmSirt2 inhibitors as novel antischistosomal agents with therapeutic potential for both curative and preventive applications. Further in vivo studies are warranted to assess their pharmacokinetic and safety profiles.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the deadliest infectious disease globally. Current TB regimens involving multidrug cocktails for ≥4 months with significant side effects leave much to be desired, with the first- and second-line drugs inhibiting only a limited number of bacterial targets. Thus, potent antimycobacterial agents with novel targets and mechanisms of action are urgently needed to overcome these limitations and the emergence of multidrug-resistant strains. To address this need, we tested a panel of cyclic sulfamate (CS) compounds and identified novel chemotypes that exhibit potent and highly selective activity against Mtb. Most importantly, multiple lines of evidence that include whole genome sequencing of spontaneous resistant mutants, cell-wall damage reporter assays, modeling of drug–target interactions, and cell wall lipid profiling support the hypothesis that these compounds kill Mtb by inhibiting KasA. KasA encodes a β-ketoacyl synthase, whose role in elongation of acyl-AcpM chains is required for the biosynthesis of mycolic acids. Despite being well validated as an essential enzyme, KasA is still an underexploited drug target in Mtb. In our work, the unchanged susceptibility of CS-resistant mutants to front-line TB drugs provides further evidence that the CS series of compounds acts via a novel mechanism of action. The knowledge gained in this study about structure–activity relationships will guide future medicinal chemistry optimization of the CS scaffold and evaluation of the in vivo efficacy of this chemical series. If successful, this novel chemotype may serve as the starting point for the development of alternative treatment options for TB.

Malaria tropica remains a major global health challenge, raising the need for new therapeutic strategies against Plasmodium falciparum. While nucleoside analogues are effective against viruses and cancer, their use against P. falciparum is limited by the lack of nucleoside kinases in this species. To overcome this, we generated and tested cell-permeable derivatives of 5-fluorodeoxyuridine triphosphate (cpFdUTP) for antiparasitic activity in infected human red blood cells. cpFdUTP rapidly and potently inhibited the proliferation of P. falciparum, arresting development at the trophozoite-to-schizont transition by stalling DNA replication, as observed in a P. falciparum nuclear cycle sensor line. Although cpFdUTP also impaired the growth of human cells, supplementation with thymidine or cell-permeable deoxythymidine triphosphate (cpdTTP) selectively rescued human cells while maintaining parasite inhibition. This identifies a potential therapeutic window for cpFdUTP in combination with thymidine, outlining a novel approach for malaria treatment.

The impact of helminthiases on global health for both humans and animals and the limited efficacy of existing drugs against these infections reinforces the urgent need for novel anthelmintic agents. On this background, in previous work we identified cinnarizine, a first-generation antihistamine, as effective anthelmintic agent against Angiostrongylus cantonensis first-stage larvae (L1) in vitro. A. cantonensis worm is the causative agent of neuroangiostrongyliasis, a condition that leads to eosinophilic meningitis with no effective treatment to date. In the present work, modifications on cinnarizine structure were designed to improve its efficacy against the larvae but keeping its ability to cross the blood brain barrier allied to improvement in the drug-like and solubility profile. A set of 11 compounds were synthesized and tested against L1 larvae, showing EC₅₀ values ranging from 9.3 to 4.2 μM. The most effective were also tested against infective third-stage larvae (L3), with EC₅₀ 18.1–8.6 μM. None of the compounds showed toxicity to both HaCat mammalian cells (at 500 μM) and Caenorhabditis elegans (at 1000 μM), indicating their high selective toxicity toward A. cantonensis. Structure–activity relationship analysis using molecular descriptors indicated that presence of two basic nitrogen atoms and balanced lipophilicity of compound 2b (EC₅₀ L1 9.3 μM; L3 8.8 μM) played the role in the anthelmintic activity, and simplified compound 3a (EC₅₀ L1 8.7 μM; L3 18.1 μM) represent a novel prototype for further modifications.