Bakteriofagi - potencijal za prevladavanje antibiotičke rezistencije

professional thesis

• Author: Tibor Klinčić
• Mentor: Gordana Maravić Vlahoviček (mentor)
• Committee member: Maja Šegvić Klarić
• Committee member: Sandra Šupraha Goreta
• Committee member: Ivana Čepelak
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; Zagreb
• Defense date and country: 2016, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Cilj istraživanja:
Cilj istraživanja je načiniti opsežan pregled dosadašnjih spoznaja i zahtjeva za razvoj i primjenu bakteriofaga kao potencijala za suzbijanje infekcija uzrokovanih rezistentnim bakterijskim sojevima.
Hipoteze istraživanja su:
1. Mehanizam djelovanja bakteriofaga razlikuje se od mehanizma djelovanja standardnih antibiotika pa razvoj rezistencije može biti odgođen ili se rezistencija može prevladati.
2. Bakteriofagi predstavljaju potencijal za izbjegavanje trenutne krize nedostatka učinkovitih antibiotika, uslijed povećanog razvoja i širenja bakterijske rezistencije.
3. Optimizacijom i razvojem bakteriofagi mogu poslužiti kao nadopuna terapiji antibioticima.
Materijal i metode:
Pregledom znanstvene literature su opisane trenutne spoznaje o bakteriofagima, njihov mehanizam biološkog djelovanja i interakcije s bakterijskim stanicama. Osim regulatornih, sagledani su i zahtjevi kakvoće te sigurnosti koje bi bakteriofagi trebali zadovoljiti. Razmatrana je terapijska širina, bakterijska rezistencija na bakteriofage, izazovi pri proizvodnji te mogućnosti modifikacije bakteriofaga. Prikazani su dosadašnji rezultati dobiveni primjenom bakteriofaga u suzbijanju bakterijskog rasta te prednosti i nedostaci u odnosu na trenutno dostupnu antibakterijsku terapiju.
Rezultati:
Predloženo istraživanje pruža uvid u dosadašnje dostupne rezultate te zahtjeve koje je potrebno zadovoljiti kako bi bakteriofagi bili korišteni kao terapija infekcija uzrokovanih rezistentnim sojevima. Interes za primjenu litičkih faga predstavlja njihova mogućnost samoumnažanja na mjestu infekcije u prisutnosti patogenih bakterija, što je potvrđeno ispitivanjem učinkovitosti in vivo. Potrebno je detaljnije utvrditi farmakološke zahtjeve takve terapije. Za proširenje terapijske širine optimalni bi bili kokteli bakteriofaga. U te svrhe potrebno je genotipski i fenotipski definirati izolate bakteriofaga, kako bi se izbjegao razvoj rezistencije kod ciljanih bakterija. Navedeno je značajno i sa sigurnosnog aspekta, da se izbjegnu neželjeni učinci na ljudsko zdravlje. Optimizacija i proizvodnja bi trebala biti u skladu sa zahtjevima dobre proizvođačke prakse uz kvalitetu ugrađenu u proizvod. Redefiniranje regulatornih zahtjeva i provođenje svih faza kliničkih ispitivanja omogućilo bi dostupnost na tržištu takvih pripravaka a) za suzbijanje bakterijskih infekcija, za koje nema drugog učinkovitog odgovora, ili b) kao nadopuna antibiotičkoj terapiji, obzirom da je utvrđen sinergizam između faga i antibiotika.
Zaključak:
Bakteriofagi predstavljaju značajan, ali trenutno nedovoljno razvijen potencijal za korištenje u terapijske svrhe za suzbijanje bakterijskih infekcija, koji se može koristiti samostalno ili pak kao potpora antibiotičkoj terapiji. Osim toga, budući da se mogu modificirati metodama genetičkog inženjerstva mogli bi poslužiti i za dostavu cjepiva ili DNA u genskoj terapiji. Smjer razvoja i potencijalnu primjenu bakteriofaga definirat će rezultati budućih multidisciplinarnih istraživanja, što će ovisiti o rezultatima kliničkih ispitivanja te potvrdi učinkovitosti i sigurne primjene kod ljudi prema regulatornim zahtjevima Europske Unije i Sjedinjenih Američkih Država.

Abstract (english)

Objectives:
The main aim is to make a comprehensive review of recent studies and requests for the development and application of bacteriophages as a potential to combat infections caused by resistant bacterial strains.
Hypotheses are:
1. Mechanism of action of bacteriophages is different from the mechanism of action of standard antibiotics and the development of resistance can be delayed or resistance can be overcomed.
2. Bacteriophages represent the potential for avoiding the current crisis due to the lack of effective antibiotics as a result of increased development and spread of bacterial resistance.
3. By optimization and development bacteriophages can be used as a supplement to antibiotics.
Material and methods:
A review of scientific literature describes the current knowledge of bacteriophages, their mechanism of biological action and interaction with the bacterial cells. In addition to regulatory, perceived are also requirements about quality and security that bacteriophages should fullfil. The therapeutic range, bacterial resistance to bacteriophages, challenges and opportunities in the production of modified bacteriophages were also concidered. Results which are obtained in use bacteriophages to combat bacterial growth so far and their advantages and disadvantages compared to currently available antibacterial therapy are also shown.
Results:
The proposed research provides insight into obtained results of scientific research and requirements which have to be met in order to make bacteriophages suitable for the treatment of infections caused by bacterial strains resistant to antibiotics. Interest in the application of lytic phages is based on their ability of selfreplication on the site of the infection and in the presence of pathogenic bacteria, as it was confirmed by examining in vivo efficacy. It is necessary to further define the pharmacological requirements of such therapy. Use of bacteriophage cocktails would represent optimal extension of their therapeutic applications. For this purpose it is necessary to define genotype and phenotype of bacteriophage isolates, in order to avoid the development of resistance in the target bacteria, as well as to avoid adverse effects on human health. Optimization of the production should be in accordance with the requirements of good manufacturing practice and quality built into the product. Redefinition of regulatory requests and pass of all clinical trials phases would allow the availability of such preparations on the market a) for the use in the control of bacterial infections, for which there is no effective response, or b) as a supplement to antibiotic therapy, based on the determined synergism between phages and antibiotics.
Conclusion:
Bacteriophages are an important, but currently not sufficiently developed potential for use in suppression of bacterial infections, that can be used alone or as support to antibiotic therapy. In addition, since they can be modified by the methods of genetic engineering, it could be possible to use them for delivery of DNA vaccines or gene therapy. Development course and potential for the use of bacteriophages will be defined by the future multidisciplinary research, which will depend on the results of clinical trials and confirmation of the efficacy and safety for use in humans according to the European Union and the United States of America regulatory requirements.

• Keywords: bakteriofagi; antibiotici; bakterijska rezistencija; bakterijska infekcija
• Keywords (english): bacteriophages; antibiotics; bacterial resistance; bacterial infection
• Language: croatian
• URN:NBN: urn:nbn:hr:163:586435
• Study programme: Title: Drug development; Study programme type: university; Study level: postgraduate specialist; Academic / professional title: sveučilišni magistar/sveučilišna magistra razvoja lijekova (sveučilišni magistar/sveučilišna magistra razvoja lijekova)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Repository: Repository of Faculty of Pharmacy and Biochemistry University of Zagreb
• Created on: 2016-03-30 15:46:22