Efficacy of newly generated short antimicrobial cationic lipopeptides against methicillin-resistant Staphylococcus aureus (MRSA) |
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| Affiliation: | 1. Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland;2. Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Tx, USA;3. Saint Louis University, St Louis, Mo, USA;1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy;2. Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy;3. Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy;4. Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Rome, Italy;5. Istituto di Anatomia Patologica, Fondazione Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy;6. Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands;7. Radboud University Medical Center, Nijmegen, the Netherlands;8. School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India;9. Amity Institute of Integrative Sciences and Health, Amity University, Gurgaon 122413, Haryana, India;10. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Philadelphia, PA 19122, USA;1. Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain;2. Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain;3. Serviço de Microbiologia Centro Hospitalar Lisboa Norte, Lisboa, Portugal;4. Laboratório de Microbiologia, Serviço de Patologia Clínica, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal;5. Laboratório de Microbiologia Clínica Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal;6. Serviço de Microbiologia, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal;7. Serviço Patologia Clínica, Centro Hospitalar Universitário São João, Porto, Portugal;8. Serviço Patologia Clínica, Hospital Infante Dom Pedro, Aveiro, Portugal;9. Serviço de Patologia Clínica, Hospital Prof. Dr. Fernando da Fonseca, Amadora, Portugal;10. Serviço de Microbiologia, Hospital Garcia de Orta, Alnada, Portugal;11. Serviço de Patologia Clínica – Microbiologia – CHUA – Unidade de Portimão, Portimão, Portugal;12. Serviço de Microbiologia do Centro Hospitalar Universitário do Porto, Porto, Portugal;13. Serviço de Microbiologia, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal;14. MSD Portugal, Paço de Arcos, Portugal;1. Jawaharlal Nehru University, New Delhi 110067, India;2. National Centre for Disease Control, Delhi 110054, India;3. V.M. Govt. Medical College, Solapur, Maharashtra, India;4. SVN Govt. Medical College, Yavatmal, India;5. Defence Research and Development Establishment, Gwalior, India;6. Indian Institute of Science Education and Research (IISER), Berhampur, India;1. Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d''Ancona 20, 20127 Milan, Italy;2. Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy;3. University Hospital Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy;1. London Research and Development Centre, Agriculture and Agri-Food Canada, London, Ontario, Canada;2. Ottawa Laboratory (Carling), Canadian Food Inspection Agency, Ottawa, Ontario, Canada;3. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada;4. Center for Structural Genomics of Infectious Diseases;5. Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada;6. Department of Biology, University of Western Ontario, London, Ontario, Canada |
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| Abstract: | IntroductionInfection caused by methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) is a serious clinical challenge and research to develop new antimicrobials is imperative.MethodsThis study investigated the in vitro and in vivo efficacy of the short cationic dialkyl lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2. The antibacterial efficacy of (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 was evaluated in representative clinical methicillin-susceptible S. aureus and MRSA strains by both in vitro (MIC, time-kill curve) and in vivo (wax worms model) approaches.ResultsThese studies revealed that both (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 have rapid bactericidal activity, with a decrease of > 3 log10 colony forming units (CFU)/mL achieved in the first 6 hours of treatment. Furthermore, (C10)2-KKKK-NH2 performed similarly to daptomycin, with a sustained bacterial killing after 24 hours. Wax worms infected and treated with these lipopeptides showed a decreased survival rate of 90% to 50% within the first day of treatment. Scanning electron microscopy determined that the effect of the short lipopeptides in S. aureus was associated with important morphological structural changes that may suggest cell membrane perturbation.ConclusionThese findings suggest that the short lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 may be potential new options for treating MRSA infections. |
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