Antimicrobial Agents and Chemotherapy最新文献_第2页

Incorporation of macrophage immune stresses into an intracellular assay of drug tolerance in Mycobacterium tuberculosis. 巨噬细胞免疫应激纳入结核分枝杆菌细胞内药物耐受性测定。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-09-11 DOI: 10.1128/aac.00795-25

Greana Kirubakar, Luana Johnston, Bom Nae Rin Lee, David G Russell, Nelson V Simwela

{"title":"Incorporation of macrophage immune stresses into an intracellular assay of drug tolerance in Mycobacterium tuberculosis.","authors":"Greana Kirubakar, Luana Johnston, Bom Nae Rin Lee, David G Russell, Nelson V Simwela","doi":"10.1128/aac.00795-25","DOIUrl":"10.1128/aac.00795-25","url":null,"abstract":"Development of new and improved tuberculosis (TB) chemotherapies is hampered by antibiotic resistance and drug tolerance by Mycobacterium tuberculosis (Mtb). Phenotypic drug tolerance, a phenomenon where Mtb populations can temporarily survive therapeutic antibiotic concentrations, represents a significant hurdle to TB treatment and is indeed one of the factors responsible for prolonged TB therapy. Assays that can identify compounds with improved efficacy against drug-tolerant Mtb are urgently required to improve TB treatment regimens. Here, we report the development of a 96-well plate assay capable of identifying anti-Mtb drugs with activity against drug-tolerant Mtb in physiologically relevant intracellular environments within macrophages. Primary murine macrophages, modified either by immunological activation or specific CRISPR/Cas9 gene knockouts to generate tolerance-inducing environments, were infected with an Mtb strain constitutively expressing luciferase. Following drug exposure, differences in bacterial survival were measured by bacterial outgrowth after lysis of the host macrophages. By monitoring Mtb luciferase in infected macrophages before, during, and after drug treatment, we confirmed earlier observations that host immune stresses trigger induction of drug tolerance. However, while host stresses induced tolerance against some anti-TB compounds, the same host stresses were synergistic with other anti-TB drugs. Our assay provides the ability to profile the activities of anti-TB drugs on bacteria in intracellular host environments, which is critical to the rational design of drug combinations that provide optimal coverage of the Mtb sub-populations in the infected host.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0079525"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039016","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}

引用次数: 0

Towards precision dosing of vancomycin in patients with allogeneic hematopoietic stem cell transplantation: a comparison of published population pharmacokinetic models. 万古霉素在异基因造血干细胞移植患者中的精确剂量：已发表的人群药代动力学模型的比较。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-08-14 DOI: 10.1128/aac.00257-25

Eva-Maria A Wansing, Emily Behrens, Nicolaus M Kröger, Claudia Langebrake, Sebastian G Wicha

{"title":"Towards precision dosing of vancomycin in patients with allogeneic hematopoietic stem cell transplantation: a comparison of published population pharmacokinetic models.","authors":"Eva-Maria A Wansing, Emily Behrens, Nicolaus M Kröger, Claudia Langebrake, Sebastian G Wicha","doi":"10.1128/aac.00257-25","DOIUrl":"10.1128/aac.00257-25","url":null,"abstract":"Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) often receive vancomycin as antibiotic treatment using therapeutic drug monitoring (TDM). TDM can be performed using a Bayesian approach, where concentration measurements are supported by a previously developed pharmacokinetic model based on a population as similar as possible to the treated patient. As a model developed in a similar population is not always available, it must be ensured that the predictive performance is not compromised. We retrospectively collected data from 121 adult allo-HSCT patients who received vancomycin treatment including trough concentration TDM between January and December 2021. Predictive performance of 21 published pharmacokinetic models was assessed by comparing the third observed vancomycin concentration per patient with the corresponding model prediction. Prediction was based on covariates alone (a priori) or covariates and TDM measurements (Bayesian). Predictive performance was quantified by a median prediction error (MPE) for accuracy and median absolute prediction error (MAPE) for precision. MPE ranged between -199.6% and 93.3% (a priori) and between -50.6% and 19.1% (Bayesian), while MAPE ranged between 31.6% and 199.6% (a priori) and between 19.8% and 53.5% (Bayesian). The Okada et al. model was one of the most accurate and precise models in the a priori (MPE: -4%; MAPE: 31.6%) and Bayesian scenario (MPE: -6.9%; MAPE: 19.8%). The model published by Okada et al. was developed in allo-HSCT patients. That may explain the high predictive performance, especially in the a priori scenario. We recommend the Okada et al. model for future TDM in allo-HSCT patients.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0025725"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854334","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}

引用次数: 0

Synergistic interaction between praziquantel and oxfendazole or fenbendazole in a murine cysticercosis model. 吡喹酮与奥芬达唑或芬苯达唑在小鼠囊虫模型中的协同相互作用。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-08-18 DOI: 10.1128/aac.00560-25

Palomares-Alonso Francisca, González-Maciel Angélica, Reynoso-Robles Rafael, Castro Nelly, Pérez-Severiano Francisca, Sánchez-Mendoza Alicia, Jung-Cook Helgi, Bravo Guadalupe, López-Muñoz Francisco

{"title":"Synergistic interaction between praziquantel and oxfendazole or fenbendazole in a murine cysticercosis model.","authors":"Palomares-Alonso Francisca, González-Maciel Angélica, Reynoso-Robles Rafael, Castro Nelly, Pérez-Severiano Francisca, Sánchez-Mendoza Alicia, Jung-Cook Helgi, Bravo Guadalupe, López-Muñoz Francisco","doi":"10.1128/aac.00560-25","DOIUrl":"10.1128/aac.00560-25","url":null,"abstract":"Up to date, the pharmacological treatment for active neurocysticercosis (NCC) includes only two drugs, praziquantel and albendazole; however, the clinical response is not always successful, due to its low bioavailability; therefore, new approaches are needed. The aim of the present study was to evaluate the pharmacological interaction between praziquantel (PZQ) and oxfendazole (OXF) in vitro; also, the drug-drug interaction between PZQ and OXF or fenbendazole (FBZ) in vivo using Taenia crassiceps metacestode was assessed. For the in vitro study, the surface of synergistic interaction (SSI) analysis was used to determine the kind of drug interaction between PZQ and OXF. Additionally, morphological and ultrastructural effects were investigated using transmission scanning electron microscopy. For the in vivo study, different doses of PZQ and FBZ or OXF were combined, and the cysticidal effect was determined. In vitro, results showed that 12 combinations exhibited synergism, and four exhibited additive effects. The 1:5 ratio of PZQ and OXF exhibited the highest synergistic effect, with an 11-fold increase in comparison to their theoretical sum. Microscopic observations revealed damage to the tegument and germinal layer; microtriches, flame cells, and muscular fibers were also affected. In vivo, results showed that PZQ + FBZ and PZQ + OXF (ratios 1:4 and 1:1, respectively) exhibited a synergistic reduction of the parasites. The findings of the present study show the potential of these combinations as a pharmacological alternative for cysticercosis treatment. Complementary studies are needed to determine their benefits in the clinical field.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0056025"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871048","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}

引用次数: 0

Transposition of Tn552-II (a Tn552 derivative) to the conjugative pCtra plasmid family in pediatric multidrug-resistant community-associated MRSA. 儿童多药耐药社区相关MRSA中Tn552- ii （Tn552衍生物）到共轭pCtra质粒家族的转位

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-09-03 DOI: 10.1128/aac.00647-25

Tsai-Wen Wan, Masaki Shintani, Kenji K Kojima, Naohiko Moriguchi, Wei-Chun Hung, Yu-Ting Wang, Lee-Jene Teng, Tatsuo Yamamoto

引用次数: 0

Therapeutic approach to difficult-to-treat multidrug-resistant enterococcal infections. 难以治疗的多重耐药肠球菌感染的治疗方法。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-09-11 DOI: 10.1128/aac.01060-24

Adrianna M Turner, Paul Kinsella, William R Miller, Glen P Carter, Truc T Tran, Benjamin P Howden, Cesar A Arias

引用次数: 0

Targeting mycobacterial transpeptidases: evaluating the roles of Ldt and PBP inhibition in suppressing Mycobacterium smegmatis. 靶向分枝杆菌转肽酶：评价Ldt和PBP抑制在抑制耻垢分枝杆菌中的作用。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-09-15 DOI: 10.1128/aac.00126-25

Mariska de Munnik, Karina Calvopiña, Patrick Rabe, Christopher J Schofield

{"title":"Targeting mycobacterial transpeptidases: evaluating the roles of Ldt and PBP inhibition in suppressing Mycobacterium smegmatis.","authors":"Mariska de Munnik, Karina Calvopiña, Patrick Rabe, Christopher J Schofield","doi":"10.1128/aac.00126-25","DOIUrl":"10.1128/aac.00126-25","url":null,"abstract":"β-lactams demonstrate promising in vitro activity against Mycobacterium species and are being explored for tuberculosis treatment; however, evidence of their in vivo efficacy versus Mycobacterium tuberculosis remains limited. To achieve broad clinically relevant potency, optimization of the classical β-lactam scaffolds or development of new or non-β-lactam inhibitors for mycobacterial transpeptidases is likely required. In mycobacteria, potential targets of β-lactams include l,d-transpeptidases (Ldts) and penicillin-binding proteins (PBPs). Reports suggest that dual inhibition of Ldts and PBPs may be necessary to achieve effective anti-mycobacterial activity, yet the specific contributions of Ldt and PBP inhibition to the β-lactam antibacterial mechanisms are poorly understood. We used fluorogenic substrate mimics to investigate the effects of β-lactams and reported LdtMt2 inhibitors on Mycobacterium smegmatis (Msm), assessing their impacts on Ldt and PBP transpeptidase activities in living cells. The results reveal a statistically significant correlation between both Ldt and PBP inhibition and Msm growth suppression; under the tested conditions, a stronger correlation between Ldt inhibition and Msm growth suppression was observed. Notably, apparent inhibition of both PBPs and Ldts was observed with all active inhibitors, though β-lactams manifest increased potency of PBP inhibition. The combination of the β-lactams meropenem and faropenem with selected LdtMt2 inhibitors manifested an additive inhibitory effect against Msm. Our results highlight the importance of further optimizing β-lactam efficacy versus mycobacterial PBPs and Ldt transpeptidases.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0012625"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063444","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}

引用次数: 0

Quality control and considering systematic MIC shifts are key when evaluating the role of mmpR5 (Rv0678) frameshifts in bedaquiline resistance. 在评估mmpR5 （Rv0678）帧移在贝达喹啉耐药中的作用时，质量控制和考虑系统的MIC移位是关键。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-08-14 DOI: 10.1128/aac.00266-25

Thomas Schön, Paolo Miotto, Varvara K Kozyreva, Matthew D Sylvester, Daniela M Cirillo, Claudio U Köser

引用次数: 0

Preclinical virology profiles of the HIV-1 capsid inhibitors VH4004280 and VH4011499. HIV-1衣壳抑制剂VH4004280和VH4011499的临床前病毒学分析

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-09-03 DOI: 10.1128/aac.00309-25

Chunfu Wang, Haichang Huang, Lourdes Valera, Kyle Parcella, Christiana Iwuagwu, Brian McAuliffe, Paul J Falk, Donald R O'Boyle Ii, Ronald E Rose, Ricardo Ramírez Padilla, Chunxiang Wu, Yong Xiong, John Kadow, Umesh Hanumegowda, Luca Sardo, Eric P Gillis, Mark Krystal, Robert A Fridell

{"title":"Preclinical virology profiles of the HIV-1 capsid inhibitors VH4004280 and VH4011499.","authors":"Chunfu Wang, Haichang Huang, Lourdes Valera, Kyle Parcella, Christiana Iwuagwu, Brian McAuliffe, Paul J Falk, Donald R O'Boyle Ii, Ronald E Rose, Ricardo Ramírez Padilla, Chunxiang Wu, Yong Xiong, John Kadow, Umesh Hanumegowda, Luca Sardo, Eric P Gillis, Mark Krystal, Robert A Fridell","doi":"10.1128/aac.00309-25","DOIUrl":"10.1128/aac.00309-25","url":null,"abstract":"With its high degree of conservation and critical role in multiple steps of the HIV-1 life cycle, the HIV-1 capsid protein presents an attractive therapeutic target. Herein, the virologic properties of the HIV-1 capsid inhibitors VH4004280 (VH-280) and VH4011499 (VH-499), including potency, mechanisms of action, and resistance profiles, are described. VH-280 and VH-499 inhibited panels of HIV-1 laboratory strains and viruses containing capsid sequences from clinical isolates with half-maximal effective concentrations in the picomolar range. Time-of-addition experiments determined that the primary block to HIV-1 replication occurred after nuclear import and before integration; however, measurements of replication intermediates by quantitative polymerase chain reaction, Gag degradation, p24 release, and virion morphology by cryo-electron microscopy indicate that VH-280 and VH-499 also block nuclear import, total reverse transcript production, integration, virion assembly, and maturation. In vitro resistance selection identified Q67H, A105E, T107D/N, and combinations of these substitutions as conferring 6- to >5,000-fold reductions in susceptibility to both compounds. Certain resistance-associated mutations selected by other capsid inhibitors also reduced susceptibility. Overall, the preclinical virology profiles and other drug-like properties support the potential of VH-280 and VH-499 as long-acting agents for HIV-1 treatment and prevention.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0030925"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940084","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}

引用次数: 0

Dual mechanism of the OXA-23 carbapenemase inhibition by the carbapenem NA-1-157. 碳青霉烯NA-1-157抑制OXA-23碳青霉烯酶的双重机制

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-08-20 DOI: 10.1128/aac.00918-25

Marta Toth, Nichole K Stewart, Pojun Quan, Md Mahbub Kabir Khan, Jonathan Cox, John D Buynak, Clyde A Smith, Sergei B Vakulenko

{"title":"Dual mechanism of the OXA-23 carbapenemase inhibition by the carbapenem NA-1-157.","authors":"Marta Toth, Nichole K Stewart, Pojun Quan, Md Mahbub Kabir Khan, Jonathan Cox, John D Buynak, Clyde A Smith, Sergei B Vakulenko","doi":"10.1128/aac.00918-25","DOIUrl":"10.1128/aac.00918-25","url":null,"abstract":"Carbapenem-resistant Acinetobacter baumannii continues to be a leading cause of life-threatening infections that result in high mortality rates. The major cause of carbapenem resistance in this pathogen is the production of class D carbapenemases, enzymes that inactivate the last resort carbapenem antibiotics, thus significantly diminishing the available therapeutic options. In this study, we evaluated the interaction of OXA-23, the most widely disseminated class D carbapenemase in A. baumannii clinical isolates, with the atypically modified carbapenem, NA-1-157. The MICs of this compound against strains producing OXA-23 were reduced from highly resistant levels observed for the commercial carbapenems meropenem and imipenem (16-128 µg/mL) to sensitive or intermediate levels (2-4 µg/mL). Kinetic studies showed that NA-1-157 inhibits the enzyme due to a significant decrease (>2,000-fold) in the deacylation rate relative to its closest structural analog, meropenem. Structural studies and molecular dynamics simulations demonstrated that inhibition is caused by both the inability of a water molecule to get close enough to the scissile bond to perform deacylation and by partial decarboxylation of the catalytic lysine residue upon formation of the acyl-enzyme intermediate.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0091825"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940099","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}

引用次数: 0

New Perspectives on Antimicrobial Agents: Sulbactam-durlobactam. 抗菌药物的新进展：舒巴坦-杜氯巴坦。

IF 4.5 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-10-01 Epub Date: 2025-08-22 DOI: 10.1128/aac.01086-24

Jason M Pogue, Jeffrey Harrington, Walaiporn Wangchinda, Keith S Kaye

{"title":"New Perspectives on Antimicrobial Agents: Sulbactam-durlobactam.","authors":"Jason M Pogue, Jeffrey Harrington, Walaiporn Wangchinda, Keith S Kaye","doi":"10.1128/aac.01086-24","DOIUrl":"10.1128/aac.01086-24","url":null,"abstract":"Infections due to Carbapenem-resistant Acinetobacter baumannii (CRAB) are a significant burden and are associated with devastating outcomes. Subsequently, CRAB is recognized as an urgent threat to human health by the United States (US) Centers for Disease Control and Prevention and is designated a critical pathogen, with the highest priority for research and development of novel treatment options, by the World Health Organization. Sulbactam-durlobactam was approved by the US Food and Drug Administration in 2023 for the treatment of Hospital Acquired and Ventilator Associated Bacterial Pneumonia caused by susceptible strains of A. baumannii, and as of 2024, is the Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections preferred treatment strategy, in combination with a carbapenem, for infections due to CRAB. In this commentary, we will dive into the preclinical and clinical evidence supporting this approval. We will further explore controversial and emerging questions related to sulbactam-durlobactam, including the necessity of carbapenem combination therapy for CRAB and the other potential therapeutic opportunities durlobactam may provide beyond A. baumannii.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0108624"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940138","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}

引用次数: 0