Sinteza in vrednotenje vezave vinilpiridinskih kovalentnih fragmentov na MurA

Duraković, Aida (author), Hrast, Martina (mentor)

Podatki o tem, koliko znanih bakterijskih sevov, ki povzročajo resne bolezni, je odporno na razne protibakterijske učinkovine, so zaskrbljujoči. Nekateri sevi so odporni celo na vse poznane protibakterijske učinkovine in okužbe s takšno bakterijo so neozdravljive. Sposobnost bakterije, da postane odporna na učinkovino, je za raziskovalce vedno izziv, kateri jih spodbudi za potrebno kontinuirno snovanje in oblikovanje novih protibakterijskih učinkovin ter odkrivanje novih tarč. Ravno izbor tarče, ki ni podvržena hitremu razvoju rezistence, in neraznolike kemijske knjižnice so glavna težava pri odkrivanju novih protibakterijskih učinkovin. Veliko število protibakterijskih učinkovin, ki se klinično že uporabljajo, zavirajo zadnje stopnje sinteze peptidoglikana. Fosfomicin pa zaenkrat edini deluje na začetne korake sinteze, tako da deluje kot časovno odvisni zaviralec MurA encima in tako zavira sintezo celične stene bakterij. Encimi Mur so esencialni za bakterijo, tako da bi potencialen zaviralec teh encimov bil baktericiden in imel širok spekter delovanja. V okviru magistrske naloge smo sintetizirali vinilpiridinske fragmente, ki kovalentno zavirajo encim MurA. Ireverzibilni kovalentni modulatorji so najbolj učinkovit način zdravljenja pri terapijah, ki zahtevajo stalno delovanje na tarčo. Načrtujemo, da bi iz teh fragmentov v prihodnosti razvili selektiven in specifičen tarčni kovalentni inhibitor. Na vinil piridinski skelet smo uvajali različne substituente z namenom preverjanja kemijskega prostora. Zaviralno delovanje in kovalenten način vezave smo določili na encimu MurA iz bakterij S. aureus in E. coli. Ključni faktor za uspeh učinkovine je primeren izbor aktivnega fragmenta, zato smo si v sklopu te naloge zadali cilj razširitve kemijske knjižnice in izbor najbolj učinkovitih in primernih aktivnih fragmentov, na katerih bo potekal nadaljnji razvoj.

• Language: Slovenian
• Keywords: MurA zaviralci, kovalentni zaviralci, fosfomicin, vinilpiridin, heterocikli, elektrofilni fragment
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2020
• PID: 20.500.12556/RUL-117207
• Publication date in RUL: 02.07.2020

Secondary language

• Language: English
• Title: Synthesis and evaluation of vinylpyridine covalent fragments

Abstract

The most concerning data regarding resistance of pathogenic bacteria to most known antibiotics, is their increasing number. Some strains are resistant to all known antibiotics, and those infections are incurable. Bacterial ability to become resistant to specific antibiotic is always a challenge for scientists, because it stimulates their constant design of new antibacterial agents and search for new possible targets. The selection of target is the hardest part of new antibacterial drug discovery, as target itself should not be a subject of fast resistance developement. Additionally, the diversity of chemical libraries is also a limiting step. The majority of currently used antibacterial drugs inhibit last steps of peptidoglycan synthesis. Fosfomycin is currently the only compound inhibiting the first step of bacterial wall synthesis by inhibiting the MurA enzyme. Mur enzymes are essential for bacteria and their inhibiton would lead to a wide spectrum antibacterial agent. Within this thesis we synthesized vinilpyridin fragments that covalently bind to MurA enzyme. Irreversible covalent modulators are the most effective way to treat illness that requires constant impact on the target. The plan was to develop a selective and specific target covalent inhibitor from our synthesized fragments. We introduced different substituents on vinylpirydin heterocycle to explore the chemical space. Enzyme inhibiton and covalent binding modes were tested on bacterial S. aureus and E. coli MurA enzyme. The crucial step for successful development of new drug is choosing the appropriate fragment. The goal of this thesis was to expand the chemical library of electrophilic fragments and to choose the most potent ones for further development into targeted covalent inhibitors.

• Keywords: MurA inhibitors, target covalent inhibitors, fosfomycin, vinylpiridine, heterocycle, electrophile warhead