ACS Infectious Diseases最新文献

{"title":"Larval Ascariasis Triggers Unresolved Anemia, Persistent Inflammation, and Chronic Pulmonary Disease after Single and Reinfection in a Dose-Dependent Manner in Mice.","authors":"Jorge Lucas Nascimento Souza, Chiara Cássia Oliveira Amorim, Camila de Almeida Lopes, Flaviane Vieira-Santos, Ana Rafaela Antunes-Porto, Fernanda Rezende Souza, Evelyn Ane Oliveira, Thaynan Cunha Vieira, Lucas Kraemer, Marcelo Eduardo Cardozo, Ramayana Morais de Medeiros Brito, Luisa Mourão Dias Magalhães, Geovanni Dantas Cassali, Ricardo Toshio Fujiwara, Remo Castro Russo, Lilian Lacerda Bueno","doi":"10.1021/acsinfecdis.5c00477","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00477","url":null,"abstract":"<p><p>Although different studies have investigated the pathophysiological aspects of ascariasis using experimental models, the long-term effects following the peak of larval migration in the lungs remain poorly understood, especially in different doses of infection, such as those that mimic better the natural infection scenario. In this study, we evaluated the impact of different infection doses (250, 1250, and 2500 eggs) and amount of exposure (single vs reinfection) on the host's immune response over an extended period. Our findings demonstrate that even the lowest dose (250 eggs) can induce persistent, though less severe, pathological damages compared to higher doses. These include anemia resulting from alveolar hemorrhage and the development of chronic pulmonary disease. Notably, while lower doses elicit a milder immune response, clinical manifestations tend to appear later, indicating a delayed pathological impact. Importantly, inflammatory infiltrates and altered cytokine levels (including Th1/Th2/Th17) were still observed in the lungs more than 100 days postinfection, even after larval clearance. The humoral immune response against <i>Ascaris suum</i> remained active for at least 100 days postinfection, with the potential for longer persistence. Notably, even with lower doses, only two exposures were sufficient to trigger an immune pattern similar to that observed at higher doses. These findings highlight the need for further investigation into the chronic inflammatory effects of <i>Ascaris</i> infection, including its impact on distant organs and its potential contribution to the development of noncommunicable diseases and comorbidities. A better understanding of these mechanisms is essential for developing improved strategies to control ascariasis in endemic areas.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming Immune Evasion in <i>Staphylococcus aureus</i>: Strategies for Rational Vaccine Design.","authors":"Khyber Shinwari, Brenda Vieira, Isabelle Ciaparin, Anders P Hakansson, Michelle Darrieux, Thiago Rojas Converso","doi":"10.1021/acsinfecdis.5c00569","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00569","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> remains one of the most elusive targets in bacterial vaccinology, primarily due to its complex immune evasion strategies and the phenomenon of immune imprinting. Despite decades of research and numerous clinical trials, no vaccine has demonstrated protective efficacy in humans. This review examines the underlying reasons for these failures and proposes a rational, integrative framework for next-generation vaccine development. Recent advances in reverse vaccinology, omics-driven antigen discovery, immunoinformatics, and artificial intelligence are highlighted as tools to identify conserved, immunogenic, and subdominant antigens. The review also discusses approaches for neutralizing virulence factors, disrupting biofilm-associated mechanisms, and circumventing dysfunctional immune memory. Particular emphasis is placed on the design of multivalent vaccine formulations capable of addressing the antigenic redundancy and immune modulation employed by <i>S. aureus</i>. By aligning systems biology with precision vaccinology, this review outlines a translational strategy to overcome the long-standing obstacles in the development of a safe and effective <i>S. aureus</i> vaccine.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and Antimicrobial Efficacy of a Bacteriophage Targeting Multidrug-Resistant <i><i>Escherichia coli</i></i>.","authors":"Tianshi Xiao, Chan Wang, Longbo Wang, Lingxian Xiang, Lin Li, Shaoqi Qu","doi":"10.1021/acsinfecdis.5c00651","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00651","url":null,"abstract":"<p><p>The emergence of multidrug-resistant (MDR) <i>Escherichia coli</i> poses a significant threat to global public health, necessitating alternative therapeutic strategies. In this study, we isolated and characterized a novel lytic bacteriophage (phage), vB_EcoM_51, from poultry farm sewage and evaluated its potential against MDR <i>E. coli</i>. Transmission electron microscopy revealed that the phage exhibits morphological features typical of the <i>Myoviridae</i> family, including a polyhedral head (∼66.62 nm) and a contractile tail (∼97.32 nm). Genome analysis indicated a double-stranded DNA virus of 167,016 bp with a GC content of 35.54%, classifying it within the <i>Tequatrovirus</i> genus. The phage showed potent lytic activity against eight <i>E. coli</i> strains and one <i>Salmonella enterica</i> strain. Stability assessments revealed broad thermal tolerance (-20 to 50 °C) and broad pH stability (pH 2-11). One-step growth kinetics analysis indicated rapid replication, with a latent period of 5 min and a burst size of approximately 212 plaque-forming units (PFU) per infected cell. In a mouse model infected with <i>E. coli</i>, phage treatment at 1 × 10⁹ PFU significantly improved survival rates, reduced bacterial loads in organs, and attenuated inflammatory responses. Collectively, these findings demonstrate that phage vB_EcoM_51 represents a promising candidate for phage therapy against MDR infections.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of α-Azacyclic Acetamide-Based Inhibitors of <i>P. falciparum</i> Na⁺ Pump (<i>Pf</i>ATP4) with Fast-Killing Asexual Blood-Stage Antimalarial Activity by Phenotypic Screening.","authors":"Arturo Casas, Leah S Imlay, Vandana Thathy, Kate J Fairhurst, Adele M Lehane, Aloysus K Lawong, Ioanna Deni, Josefine Striepen, Seungheon Lee, Ashwani Kumar, Chao Xing, Hanspeter Niederstrasser, Bruce A Posner, Benoît Laleu, Susan A Charman, David A Fidock, Joseph M Ready, Margaret A Phillips","doi":"10.1021/acsinfecdis.5c00436","DOIUrl":"10.1021/acsinfecdis.5c00436","url":null,"abstract":"<p><p>Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage <i>Plasmodium falciparum</i> parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na⁺ regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the <i>P. falciparum</i> Na⁺ pump (<i>Pf</i>ATP4). <i>Pf</i>ATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na⁺ concentration. Resistance selections on <i>P. falciparum</i> parasites with two α-azacyclic acetamide analogs identified mutations in <i>Pf</i>ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming <i>Pf</i>ATP4 as the target. <i>Pf</i>ATP4 is a well-established antimalarial target, and identification of additional <i>Pf</i>ATP4 inhibitors provides alternative avenues to disrupt its function.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Essential Oil–Antibiotics Synergistic Delivery Strategy via Phenylboronic-Acid-Functionalized Liposomes for Targeted Treatment of MRSA Pneumonia","authors":"Qianqian Guo*,&nbsp;Zhenxia Wu,&nbsp;Buhui Tao,&nbsp;Ling Tao,&nbsp;Qian Wang,&nbsp;Chao Huang,&nbsp;Yang Gao,&nbsp;Yu-e Wang,&nbsp;Xingjie Wu,&nbsp;Ying Chen,&nbsp;Ting Guo* and Xiangchun Shen*,&nbsp;","doi":"10.1021/acsinfecdis.5c00438","DOIUrl":"10.1021/acsinfecdis.5c00438","url":null,"abstract":"<p >Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-induced pneumonia has become a major global public health challenge due to its high mortality and drug resistance. Essential oils, derived from plants, offer a promising solution to combat resistance owing to their low cytotoxicity and multitarget antimicrobial properties. This study designed a phenylboronic acid (PBA)-functionalized liposomal codelivery system (P-Lip@CE) to reverse MRSA resistance by synergistically delivering cefazolin sodium (Cefas) and <i>Alpinia zerumbet</i> essential oil (EOFAZ). The dual-drug system exhibited good storage stability, biocompatibility, and tolerance to diverse biological environments. EOFAZ enhanced the antibacterial efficacy of Cefas by disrupting the bacterial membrane integrity and reducing its minimum inhibitory concentration (MIC) by 8-fold. P-Lip@CE showed strong bacterial adsorption due to the interaction between P-Lip and bacteria, with the in vitro MIC of P-Lip@CE being 8-fold and 33-fold lower than those of free Cefas and EOFAZ, respectively. In an MRSA-infected pneumonia model, P-Lip@CE effectively promoted tissue repair via intranasal and oral administration. This synergistic delivery strategy demonstrated a simple but effective technology for combating drug-resistant infections, allowing for reduced antibiotic dosages and the option for multiroute administration.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 9","pages":"2553–2567"},"PeriodicalIF":3.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Engineering Short Antimicrobial Peptides to Specifically Target Fusobacterium nucleatum in the Mixed Microbial Population”","authors":"Zhao Liu,&nbsp;Yijie Wang,&nbsp;Chen Zhang,&nbsp;Yongshuai Yang,&nbsp;Junfeng Zhang,&nbsp;Zhaoxia Wang*,&nbsp;Kaiyang Lim* and Chun Loong Ho*,&nbsp;","doi":"10.1021/acsinfecdis.5c00663","DOIUrl":"10.1021/acsinfecdis.5c00663","url":null,"abstract":"","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 9","pages":"2644–2645"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent Irreversible Inhibitors of Tetracycline Destructases","authors":"Ruihao Li,&nbsp;Yao-Peng Xue,&nbsp;Steven T. Le,&nbsp;Wai Kwan Tang,&nbsp;Niraj H. Tolia*,&nbsp;Gautam Dantas* and Timothy A. Wencewicz*,&nbsp;","doi":"10.1021/acsinfecdis.5c00322","DOIUrl":"10.1021/acsinfecdis.5c00322","url":null,"abstract":"<p >Next-generation tetracycline antibiotics are threatened by an emerging resistance mechanism ─ enzymatic inactivation. The relevant enzymes ─ tetracycline destructases (TDases) ─ are structural homologues of class A flavin monooxygenase (FMO) that oxidize tetracycline antibiotics, leading to various inactive degradation products. Small molecule inhibitors of antibiotic-inactivating enzymes are critical clinical therapeutics used to manage bacterial resistance with combination therapy. While reversible TDase inhibitors have been reported, we sought to develop covalent inhibitors that are better aligned with clinically effective covalent β-lactamase inhibitors. Here, we report the design, chemical synthesis, and biochemical characterization of the first covalent irreversible inhibitors of TDases based on C9-derivatives of anhydrotetracycline (aTC). The reactive warheads were installed via a one-step Mannich reaction linking either an <i>N</i>-(1-methyl)cyclopropylamine or <i>N</i>-propargylamine group to the C9-position of the aTC D-ring via an amino methylene linkage. We also synthesized two nonspecific FMO inhibitors, <i>N</i>-(1-methyl)cyclopropylbenzylamine (<b>1</b>) and <i>N</i>-methyl-<i>N</i>-benzyl-propargylamine (<b>2</b>) as mechanistic probes to distinguish reactivity with the essential FAD cofactor in TDases via one- or two-electron transfer pathways, respectively. We evaluated the compounds as potential inhibitors of representative TDases from the two major classes─<i>Type 1</i> (TetX6 and TetX7) and <i>Type 2</i> (Tet50). The aTC-based compounds <b>3</b>-<b>5</b> inhibited both <i>Type 1</i> and <i>Type 2</i> TDases with notable differences in potency and inhibition mechanism. The inhibition of <i>Type 1</i> TDases was more potent but reversible with no time dependence. The inhibition of <i>Type 2</i> TDases was time-dependent and irreversible even after exhaustive dialysis, consistent with a covalent mechanism of inhibition. Molecular modeling of the inhibitors supports unique inhibitor binding modes for <i>Type 1</i> and <i>Type 2</i> TDases that are consistent with the observed differences in the inhibition modes. Blue light irradiation of the <i>Type 2</i> TDase enhanced this reactivity. Treatment of Tet50 with probe molecules <b>1</b> and <b>2</b> under blue light exposure enabled the identification of covalent FAD adducts via mass spectrometry that are consistent with the expected one- and two-electron transfer reaction modes of the cyclopropylamine and propargylamine warheads with the FAD cofactor. At concentrations as low as 2 μg/mL, the aTC-based covalent inhibitors <b>3</b>-<b>5</b> recovered tetracycline activity against <i>E. coli</i> overexpressing TDases. Our findings suggest that the inhibition of TDases through covalent trapping of the FAD cofactor is a viable strategy for overcoming TDase-mediated antibiotic resistance.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 9","pages":"2476–2490"},"PeriodicalIF":3.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Approach for Chagas Disease Screening Using Serum Infrared Spectroscopy and Machine Learning Algorithms","authors":"Matthews Martins,&nbsp;Ângelo Antônio Oliveira Silva,&nbsp;Felipe Silva Santos de Jesus,&nbsp;Emily Ferreira Santos,&nbsp;Daniel Dias Sampaio,&nbsp;Wanderson Romão,&nbsp;Fred Luciano Neves Santos* and Valerio G. Barauna,&nbsp;","doi":"10.1021/acsinfecdis.5c00377","DOIUrl":"10.1021/acsinfecdis.5c00377","url":null,"abstract":"<p >Chagas disease (CD) affects an estimated 6–7 million people worldwide, predominantly in Latin America. However, migration has expanded its geographic reach. Diagnosing chronic CD is challenging due to low parasitemia and the limitations of existing serological assays. This study evaluates the diagnostic potential of attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy combined with machine learning (ML). A total of 100 serum samples (49 CD-positive, 51 negative controls) were analyzed using ATR-FTIR spectroscopy under two conditions: (i) dry analysis (air-dried samples) and (ii) wet analysis (direct serum analysis). Spectral data were processed using ML algorithms, including logistic regression (LR), partial least-squares discriminant analysis (PLS-DA), random forest (RF), and extreme gradient boosting (XGBoost) for sample classification. The best-performing models were LR for dry data set (accuracy and F1-score: 93%) and XGBoost for the wet data set (accuracy and F1-score: 87%). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.99 and 0.92 for the dry and wet data sets, respectively. The robustness and reliability of the model were confirmed through permutation tests. These results demonstrate that ATR-FTIR spectroscopy combined with ML is a promising diagnostic tool for CD. Despite the study’s limited sample size, results suggest this approach could serve as a cost-effective alternative to conventional serological assays, particularly in resource- constrained settings. Further validation with larger data sets and diverse control groups is essential to assess its specificity and clinical applicability. If successful, this method could significantly enhance early diagnosis and improve disease managements strategies for CD.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 9","pages":"2515–2522"},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.5c00377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activity of Antibacterial/Antifungal Compounds against the Protozoan Parasite, Toxoplasma gondii","authors":"Davinder Singh,&nbsp;Melissa A. Sleda,&nbsp;Satish R. Malwal,&nbsp;Akanksha M. Pandey,&nbsp;Yiyuan Chen,&nbsp;Ruijie Zhou,&nbsp;Feyisola Adewole,&nbsp;Katie Sadowska,&nbsp;Oluseye K. Onajole,&nbsp;Silvia N. J. Moreno* and Eric Oldfield*,&nbsp;","doi":"10.1021/acsinfecdis.5c00609","DOIUrl":"10.1021/acsinfecdis.5c00609","url":null,"abstract":"<p >We investigated the antiparasitic activity of several antimicrobial drug leads against <i>Toxoplasma gondii</i> tachyzoites and, in one case, bradyzoites. Carbazole and phenylthiazole aminoguanidine anti-infectives, originally developed as antibacterial and antifungal agents, showed potent activity, with IC₅₀ values as low as 2 μM. This potency was comparable to that observed with the tuberculosis drug candidate SQ109 and a series of its analogs. Notably, SQ109 also significantly reduced the viability of in vivo-derived bradyzoites. All compounds acted, at least in part, as protonophore uncouplers by collapsing the ΔpH component of the proton motive force. Furthermore, SQ109 and the tetrahydrocarbazole (THCz) compounds disrupted the mitochondrial membrane potential in <i>T. gondii</i> tachyzoites. While SQ109 is known to activate macrophages to an M1 phenotype, we observed no significant difference in its activity against <i>T. gondii</i> grown in fibroblasts versus macrophages, likely due to the parasite’s residence within the protective parasitophorous vacuole. We also examined correlations between compound activity against the yeast <i>Saccharomyces cerevisiae</i>, and the bacterium <i>Mycobacterium smegmatis</i>, finding significant correlations between the collapse of the proton motive force and antiproliferative activity. Taken together, our findings underscore the potential of these antimicrobial agents as promising leads for the development of new antiparasitic therapies against <i>T. gondii</i><i>.</i></p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 9","pages":"2617–2627"},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deploying Soft Drugs in the Fight against MRSA with Detailed Biological Evaluation of 4-(n-Alkoxy)-phenoxy Betaine Amphiphiles Active against MDR Staphylococcus aureus and Enterococcus sp.","authors":"Dharmendra Katiyar,&nbsp;Abdul Akhir,&nbsp;Grace Kaul,&nbsp;Deepanshi Saxena,&nbsp;Tejender S. Thakur* and Sidharth Chopra*,&nbsp;","doi":"10.1021/acsinfecdis.5c00267","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00267","url":null,"abstract":"<p >Antimicrobial resistance is one of the major challenges faced worldwide by the healthcare systems, negatively impinging upon global health and the economy. Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), which causes skin and mucosal infections, contributes to 64% more death as compared to drug-susceptible infections, which forces researchers to continuously search for new antimicrobials. In this context, we report the synthesis and antimicrobial activity of novel amphiphilic cationic 1,4-alkoxy-phenol derivatives. We synthesized a library of 12 small amphiphilic compounds containing an <span>l</span>-carnitine or betaine as a cationic headgroup and investigated the effect of the hydrocarbon chain length on the antimicrobial activity against a critical and high-priority human pathogen panel. The amphiphilic molecules with a C-10 alkyl chain length (<b>2f</b> and <b>3f</b>) showed substantial antibacterial activity at very low concentrations (1–2 μg/mL). Based on low cytotoxicity (Selectivity Index 20) and MIC of amphiphilic series, we further explored <b>3f</b>, which shows a concentration-dependent bactericidal activity at 10× MIC; it completely wiped out <i>S. aureus</i> ATCC 29213 at 1 h, and when combined with daptomycin, it showed a reduction of ∼6 log₁₀ CFU/mL as compared with untreated at 24 h against <i>S. aureus</i> ATCC 29213 even at 1× MICs. In order to discriminate between nonspecificity in detergent-like action, we further determined the CMC of 3f and found that it is 36-fold higher than MIC, thus further emphasizing its specificity. <b>3f</b> exhibits biofilm eradication properties that are comparable to levofloxacin and better than vancomycin while intracellular killing efficacy of <b>3f</b> was found to be better than vancomycin and similar to levofloxacin. When tested <i>in vivo</i> in the murine skin infection model, it shows activity comparable to fusidic acid as it reduces ∼2 log₁₀ CFU/g compared with that untreated. Considering the potent antimicrobial properties of <b>3f</b>, we hypothesize that it opens up a new avenue for discovery and development of novel antimicrobials active against MDR <i>S. aureus</i> and <i>Enterococcus</i> sp.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 9","pages":"2434–2445"},"PeriodicalIF":3.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}