A unique strategy for reshaping the antibiotics model: chemokine-inspired therapeutics for targeting the host and pathogen to counter infections caused by multidrug-resistant bacteria

重塑抗生素模型的独特策略：针对宿主和病原体的趋化因子启发疗法，对抗多重耐药细菌引起的感染

• 批准号: 10676878
• 负责人: MOLLY A HUGHES
• 金额: $ 61.31万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676878
• 关键词: Address; Adoption; Affect; Amino Acids; Animal Experimentation; Anti-Infective Agents; Antibiotics; Antimicrobial Resistance; Area; Bacteria; Biological; Biological Process; Biology; CXCL10 gene; Cell physiology; Cells; Chemistry; Clinical; Clinical Management; Collection; Communicable Diseases; Data; Dermal; Development; Disease Progression; Dose; Equilibrium; Etiology; Exhibits; Foundations; Gram-Positive Bacteria; Health; Host Defense; Human; Immune; Immunotherapy; In Vitro; Individual; Infection; Injury; Intention; Invaded; Investigation; Klebsiella pneumoniae; Laboratories; Lead; Life; Measures; Mediating; Methodology; Microbe; Modeling; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Natural regeneration; Outcome; Pattern; Peptide Hydrolases; Peptides; Periodicity; Phenotype; Physiological; Pneumonia; Process; Productivity; Recovery; Regenerative Medicine; Research; Research Activity; Resistance; Resources; Shapes; Surgical Wound Infection; System; Technology; Testing; Therapeutic; Treatment Efficacy; Wound Infection; antimicrobial; arms race; bacterial resistance; bactericide; cancer therapy; carbapenem-resistant Enterobacteriaceae; chemokine; clinically significant; combat; combat wound; combinatorial; cost; cytotoxicity; dosage; drug discovery; efficacy evaluation; fortification; healing; healthcare-associated infections; human pathogen; immune clearance; immunotoxicity; in vivo; in vivo regeneration; innovation; insight; lead series; man; methicillin resistant Staphylococcus aureus; microorganism; mortality; mouse model; multi-drug resistant pathogen; next generation; novel therapeutics; pathogen; pathogenic bacteria; pre-clinical; pressure; receptor; regenerative; therapeutic development; therapeutic target; tissue repair; usability; wound; wound bed; wound healing; wound treatment

PROJECT SUMMARY Background: Antibiotics have traditionally been developed and deployed as stand-alone antimicrobials, comprising a single destructive pressure to kill microorganisms. While initially successful, this model presents minimal barrier against the emergence of resistance. Thus, the arms race between man and microbe has reached a perilous tipping point: many clinically-significant bacterial pathogens are increasingly resistant to multiple, and in some cases all, available antibiotics. For nearly 15 years the Hughes laboratory and colleagues have investigated the antimicrobial actions of the human chemokine CXCL10. This multifunctional effector mediates receptor-dependent host-targeted activities, including immune defense and regenerative processes, as well as direct bactericidal effects against multidrug-resistant (MDR) bacterial pathogens. Towards harnessing the therapeutic utility of these actions, our collaborative team has divided the principal biological activities of CXCL10 into a pair of individually-tailored derivatives: peptide P1 exerts host-targeted effects, while peptide D8 kills diverse MDR bacteria. We hypothesize that this exciting breakthrough provides a tunable arrangement from which to balance and apply a 'multi-fold' therapeutic strategy that directly kills invading bacteria, enlists immune defense to combat infection, and promotes host recovery. Approach: To test this innovative concept, we propose to deploy CXCL10-derived peptides to counter wound/surgical site infections, the most common and costly type of healthcare-associated infection. Using an established murine model amenable to measuring wound healing and infection outcomes, we will: [Aim 1] distinguish peptide P1 dose/dosage strategies for affecting host-immune engagement and the promotion of tissue repair/regeneration; and [Aim 2] determine the therapeutic efficacy of bactericidal peptide D8, unaided and together with peptide P1, against wound infections caused by carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus (MRSA), clinically-challenging etiologic agents of wound infections in humans. Animal research will be enriched by in vitro studies that elaborate physiologic and bactericidal modes-of-action, measure peptide biostability, assess potential lead-peptide cytotoxicity, and evaluate the emergence of peptide D8-resistant bacterial phenotypes. The proposed research will be accomplished by a cross-disciplinary group of collaborators with demonstrated expertise in the areas of clinical infectious diseases, regenerative medicine, immunotherapy, peptide chemistry, and therapeutics development. Outcomes: The proposed research activities are expected to yield entirely new anti-infective and regenerative technologies, and establish a unique paradigm whereby antimicrobial therapies not only kill pathogens, but also conscript host processes to combat infection, diversify selective pressures, and promote recovery. The original resources and compelling preliminary data described in this application attest to the feasibility and likelihood of successfully achieving these outcomes towards addressing the mounting burden of MDR bacteria.

项目总结

项目成果

The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner.

• DOI: 10.3390/v13061062
• 发表时间: 2021-06-03
• 期刊: Viruses
• 作者: Callahan V;Hawks S;Crawford MA;Lehman CW;Morrison HA;Ivester HM;Akhrymuk I;Boghdeh N;Flor R;Finkielstein CV;Allen IC;Weger-Lucarelli J;Duggal N;Hughes MA;Kehn-Hall K
• 通讯作者: Kehn-Hall K