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BEDREHELSE-Bedre helse og livskvalitet

Antimicrobial peptides (bacteriocins) as alternative to conventional antibiotics

Alternativ tittel: Nye antimikrobielle peptider for bekjemping av antibiotikaresistente infeksjoner

Tildelt: kr 7,8 mill.

Mange hudinfeksjoner er forårsaket av bakterielle patogener, og behandling av disse infeksjonene har blitt stadig vanskeligere på grunn av økende antibiotikaresistens. Dette gjelder også for personer med spedalskhet eller diabetes som ofte lider av alvorlige infeksjoner i beina. Begge typer infeksjoner kan ha forskjellige grader av alvorlighet, men i noen alvorlige tilfeller er amputasjon det eneste alternativet for å forhindre ytterligere infeksjon. To av de vanligste patogenene i disse infeksjonene er Staphylococcus aureus og Pseudomonas aeruginosa. Disse to er blant de patogenene som oftest utvikler antibiotikaresistens, noe som gjør at terapeutiske behandlinger er problematiske. Vi har jobbet med en gruppe antimikrobielle peptider (såkalte bacteriociner) som har svært god aktivitet mot mange viktige Gram-positive og Gram-negative patogener som enterokokker, listeria, stafylokokker, streptokokker, Salmonella spp, Escherichia coli og Pseudomonas aeroginosa. Noen av disse bacteriocinene er godt karakterisert og har andre virkningsmekanismer enn tradisjonelle antibiotika, og kan dermed drepe både patogenene og deres antibiotikaresistente derivater, som for eksempel meticillinresistent S. aureus (MRSA) og vancomycinresistent Enterococcus (VRE). I dette prosjektet utvikles disse til bruk i antimikrobielle behandlinger, spesielt for behandling av infeksjoner forårsaket av antibiotikaresistente patogener.

Treatment of skin infections caused by bacterial pathogens has become very challenging due to antibiotic resistance. Skin infections are, for example, highly problematic as secondary infections in leprosy patients and patients with diabetic wounds. The most common pathogens associated with these infections were found to be staphylococci, including Staphylococcus aureus (including MRSA). As an alternative to common antibiotics, the project investigated the potential for developing bacteriocins, a group of antimicrobial peptides, into drugs for medical use to combat skin-infections caused by these pathogens. In the project, bacteriocins with activity against MRSA were identified and there stability and mechanism were characterized. Protocols were developed to study the effect of bacteriocins on biofilms formed by relevant pathogens and a murine model to study the effect of bacteriocin treatment on MRSA skin infections was developed. These models were used to demonstrate that bacteriocins and synergistic combinations of bacteriocins and antibiotics could be effective in treatment of biofilms and murine skin infections using different topical peptide formulations with high antimicrobial efficiency, in vivo and in vitro, against Gram-positive bacterial pathogens. Taken together, the project has developed protocols and provided results which has contributed in the development of bacteriocins a potential new, antimicrobial for exploitation in medicine.

Many skin infections are caused by bacterial pathogens and treatments of these infections have become very challenging in recent years due to antibiotic resistance. This is true for people with leprosy or diabetes who often have severe infections in the lower limbs. Improper care or lack of awareness regard to care of the feet without skin sensation (anaesthetic) lead to ulceration and secondary infections of the wound which in many cases tend to be chronic and recurrent. Both types of infections may have different Levels of morbidity but in some serious cases amputation is the only option to prevent further infection. Common pathogens in these two types of infections are two microorganisms, Staphylococcus aureus and Pseudomonas aeruginosa. These two are also amongst the most frequent antibiotic resistant-pathogens leaving therapeutic treatments ineffective in diverse topical and systemic infections. We have been working on a group of antimicrobial peptides (called bacteriocins) with very potent activity, against many important Gram-positive and Gram-negative pathogens such as enterococci, listeria, staphylococci, streptococci, Salmonella spp, Escherichia coli and Pseudomonas aeroginosa. Some of these are well characterised and known to apply modes of action different from traditional antibiotics, and hence they can readily kill pathogens as well as their antibiotic-resistant derivatives such as methicillin-resistant S. aureus (MRSA) and vancomycin- resistant Enterococcus (VRE). These compounds hold a great potential in diverse antimicrobial interventions, especially in dealing with antibiotic resistant pathogens. In this project proposal we will develop these antimicrobial peptides into drugs for medical use, with special focus on treatments of secondary infections in leprosy patients and in patients with diabetic wounds.

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