ACS Infectious Diseases最新文献

The obstinatproblem of drug resistancein tuberculosis (TB) requiressustained efforts in the search for new drug molecules. Building onour previously developed synthetic hybrid compound, UH-NIP-16, whichdemonstrated anti-Mycobacterium tuberculosis (M.tb) activity, we synthesized and evaluated 15new derivatives to improve its potency. Among these, two lead compounds,UN-7 and UN-14, bearing hydrogen and methyl substitutions at the sixthposition, respectively, along with a 2-phenoxy moiety, exhibited a∼5-fold reduction in MIC₅₀ values across laboratory,clinical, and multidrug-resistant M.tb strains relativeto UH-NIP-16. Both compounds displayed a bacteriostatic mechanismof action and exhibited predominantly additive or indifferent interactionprofiles in combinatorial antitubercular studies. Importantly, UN-7and UN-14 showed minimal cytotoxicity toward mammalian cells and effectivelyreduced intracellular bacterial burden in an in vitro infection model. A coupled enzymatic assay revealed that UN-7 andUN-14 inhibited mycobacterial shikimate kinase (Mt-SK) activity byapproximately 65%, a target not inhibited by the parent compound UH-NIP-16. In silico ADMET analyses indicated several favorable drug-likenessproperties despite predicted liabilities, including Ames mutagenicityand low aqueous solubility. Collectively, these findings identifyUN-7 and UN-14 as structure–activity relationship (SAR)-guidedderivatives of the UH-NIP-16 scaffold with improved antimycobacterialactivity and promising potential for further antitubercular lead development.

Systemicmultidrug-resistant bacterial infections have become aglobal public health priority due to the diminished efficacy of standardantibiotic regimens and can lead to sepsis, which is among the leadingcauses of death (11 million/year) and years of lost life worldwide.We report an effective and well-defined antibiotic equimolar mixtureof the platanosides 1–4 that is as effective as its constituentparts and is active against multidrug-resistant Staphylococcus and Streptococcus spp. The platanosides can beeasily and inexpensively manufactured in good purity from sycamoretree (Platanus spp.) leaves, making them a viableoption as a drug to control multidrug-resistant infections in low-and middle-income countries. The platanosides 1–4 exhibitedactivity against clinically derived Staphylococcus aureus (methicillin-resistant, vancomycin-resistant,and vancomycin-intermediate) with minimal inhibitory concentrationvalues of 0.5–16 μg/mL. The minimal inhibitory concentrationvalues against clinically derived Streptococcus spp.were 2, 1, 0.06, and 1 μg/mL against Streptococcus mitis, Streptococcus paramsanginis, Streptococcus gordonii, and Streptococcus pneumoniae, respectively. Time-killstudies of the platanosides are reported. The proposed molecular targetsand unique polypharmacology of the platanosides 1–4 are alsodiscussed.

Thecontinued emergence of SARS-CoV-2 variants worldwide underscoresthe need for effective measures to combat the current and future outbreaks.The receptor-binding domain (RBD) of the spike glycoprotein playsa critical role in viral entry and represents a highly immunogenictarget. In this study, we generated a mouse-derived single-chain variablefragment (scFv) phage display library against the RBD of the SARS-CoV-2spike protein. Peptide ELISA-based epitope mapping demonstrated thatselected monoclonal scFv phages exhibited broad epitope recognitionand reactivity across multiple recently reported variants. In a SARS-CoV-2pseudovirus neutralization assay, scFv C4 showed potent neutralizingactivity against the wild-type, Gamma, and Delta variants, with IC₅₀ values below 4 μg/mL. These findings highlight thepotential utility of these scFvs as candidate reagents for the developmentof improved diagnostic platforms and as scaffolds for next-generationmonoclonal antibody-based therapeutics.

Influenza, an acute respiratory infectious disease causedby influenzaviruses, poses a serious public health threat with high infectivityand virulence. Existing antivirals suffer from numerous limitations,such as the frequent emergence of drug resistance and inconvenientadministration, highlighting the urgent need for the development ofnext-generation anti-influenza agents. As a core component of theRNA-dependent RNA polymerase (RdRp) complex, the PB2 subunit mediatescap binding in the cap-snatching process, a prerequisite for viralmRNA transcription. Owing to its indispensable biological roles, highsequence conservation, and distinct structural differences from hostproteins, PB2 serves as an attractive therapeutic target for antiviraldrug development. Recently, the approval of onradivir, the first-in-classPB2 inhibitor, has not only validated the scientific rationale andfeasibility of drug discovery targeting the PB2 subunit but also underscoredthe considerable clinical potential of this novel class of agents.In this review, we systematically summarize the research advancesin PB2 inhibitors and discuss the challenges and prospects for theirbroader clinical application, with the aim of providing new insightsinto the development of novel anti-influenza drugs.

Staphylococcus aureus isa leadingcause of antibiotic-resistant infections worldwide. Therefore, thereis a constant need to develop new growth inhibitors. Pentamidine analogs(PAs) composed of thiourea-linked amidines were evaluated for activityagainst methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria. S. aureus, MRSA, Staphylococcus epidermidis, Streptococcus pyogenes, Mycobacterium, and Bacillus were highly susceptible with minimal inhibitory concentration (MIC)values ranging from 1.56 to 6.25 μM, whereas Enterococcus species and Clostridioides difficile were not as susceptible with MICs of 50to ≥100 μM. For S. aureus, MRSA and VISA strains, PAs showed ∼4-fold lower MICs whencompared to pentamidine (PNT). The concentration of PAs needed tolyse 50% of red blood cells (HC₅₀) was ∼16–32-foldhigher than their corresponding MICs. For PNT, a lower HC₅₀/MIC range of 1.25–5 was observed. Approximately 60% of MRSAwas cleared from infected Caenorhabditis elegans by the PAs. PAs also provided 100% protection in a septicemia modelof infected mice. Morphological changes induced by these compoundsindicate disruption of cell membrane integrity, where >80% of treatedbacterial cells took up propidium iodide in a permeation assay. Importantly,there was a lack of resistance observed with the PAs, compared tothe fairly rapid and stable resistance occurrence for drugs commonlyused to treat S. aureus infection.These results reflect the potential of such compounds as potentialnew tools to optimize and combat the menace of drug-resistant S. aureus.

Theemergence of resistance to most clinically used antimalarialsnecessitates the discovery of new chemotypes. A phenotypic screenagainst asexual Plasmodium falciparum identified the 2-amino-3,4-dihydroquinazoline scaffold, previouslydeveloped as a β-secretase 1 inhibitor for Alzheimer’sdisease. Evaluation of hit analogues against malarial aspartyl proteasesrevealed potent inhibition of plasmepsin X. Structure-activity analysisshowed that key motifs on the hit scaffold are required for drivingbiochemical and antimalarial but are associated with poor selectivityagainst human aspartyl proteases and low metabolic stability. PlasmepsinX was validated as the molecular target through forward genetics,activity against mutant parasites, and inhibition of plasmepsin Xsubstrate processing. 2-Amino-3,4-dihydroquinazoline analogs exhibitmoderate asexual killing rates, low-to-moderate resistance risk, nocross-resistance with multidrug-resistant strains, and transmission-blockingactivity. Further optimization of potency and metabolic stabilitywill be required to achieve in vivo efficacy and realize the potentialof this antimalarial class.

Antimicrobialresistance (AMR) is a critical threat to global publichealth, with emerging resistance to Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), often referred to as a silent pandemic. Despite ongoingefforts in the fight against AMR, the drug discovery pipeline remainsunderdeveloped, highlighting the urgent need to explore natural andsynthetic approaches. Cannabinoid-inspired natural products representan underexplored chemical space with antimicrobial potential. Herein,we report an efficient, scalable, and enantioselective synthesis andantimicrobial evaluation of epi-perrottetinene (epi-PET), an unnatural bibenzyl-based cannabinoid analogof liverwort-derived perrottetinene. The synthetic strategy employsinexpensive starting materials and a Lewis acid-mediated Friedel–Craftscyclization to enable regioselective access to both Δ⁸- and Δ⁹-epi-PET isomers. Biologicalevaluation revealed potent antibacterial activity against Gram-positivepathogens, with particularly strong efficacy against drug-sensitiveand drug-resistant S. aureus strains,including MRSA clinical isolates. Notably, the lead compound E exhibited remarkable activity, with MIC values ≤1.2 μg/mL. Compound E remained effective againstefflux pump-overexpressing strains and bacterial biofilms and eradicatedintracellular bacteria, while displaying low hemolytic activity (3.4%of rabbit erythrocytes) and minimal cytotoxicity toward mammaliancell lines (N2a and RAW). Mechanistic studies indicate that bacterialmembrane disruption is a key contributor to the observed bactericidalactivity, consistent with rapid killing and a low propensity for resistancedevelopment. The work establishes epi-perrottetineneas a promising cannabinoid-inspired antibacterial scaffold and highlightsthe potential of nonclassical cannabinoids as a source of new chemicalmatter for addressing antimicrobial resistance.

Theglobal health crisis of antibiotic-resistant bacteria necessitatesthe development of novel antimicrobial agents. Natural antimicrobialpeptides (AMPs) represent a promising therapeutic strategy, but theirsusceptibility to proteolytic degradation in vivo severely limitstheir clinical application. Peptoids, or N-substitutedglycine oligomers, have emerged as a robust biomimetic alternative.By shifting the side chain from the α-carbon to the backbonenitrogen atom, peptoids lack amide hydrogen donors, rendering themresistant to protease hydrolysis while maintaining a peptide-mimeticarchitecture. In this review, we first compare synthetic strategies(solid-phase synthesis versus solution polymerization) and outlinekey molecular design principles that govern antimicrobial activityand biocompatibility. We further assess self-assembled supramolecularstructures that confer emergent properties, ranging from enhancedmembrane penetration to stimuli-responsive release. Finally, we discussprevailing challenges and propose future directions for translatingthese promising materials into effective antimicrobial therapies.Beyond combining recent advances, this review establishes a molecular-to-assemblyframework to guide the design of next-generation antimicrobial agents.