Primerjalna analiza fizikalno-kemijskih lastnosti, spektra delovanja in učinkovitosti protibakterijskih učinkovin

Kroflič, Nikita (avtor), Frlan, Rok (mentor)

Odpornost bakterij na antibiotike predstavlja vse večji zdravstveni problem po vsem svetu. Vzroki za njen nastanek so najpogosteje genetske mutacije, prekomerna raba antibiotikov in uporaba antibiotikov v živinoreji. Rezistenca se kaže kot zmanjšana ali povsem odsotna občutljivost bakterij na antibiotike, kar vodi do neučinkovitega zdravljenja. V magistrski nalogi smo se osredotočili na nove antibiotike z inovativnimi mehanizmi delovanja, ki so bili odobreni ali pa so se nahajali v II ali III fazi kliničnega razvoja med letoma 2020 in 2025. Cilj naloge je bil izvesti kritičen pregled kliničnih študij za štiri izbrane učinkovine (zoliflodacin, gepotidacin, lefamulin in rifasutenizol), oceniti njihovo varnost, učinkovitost in potencial za interakcije z drugimi zdravilnimi učinkovinami ter primerjati njihove fizikalno-kemijske lastnosti z že uveljavljenimi antibiotiki. Iskanje strokovne literature je potekalo v prosto dostopnih spletnih podatkovnih bazah, pri čemer je kot osnovni vir podatkov služila baza MEDLINE. Podatke o afiniteti obravnavanih učinkovin do citokromov P450 smo pridobili s pomočjo podatkovne baze ChEMBL. Vpliv na tarče, povezane z varnostjo, smo ocenjevali preko afinitete do kalijevih kanalčkov in vpliva na celično linijo HepG2 (ocena tveganja za podaljšanje intervala QT in hepatotoksičnost). Na podlagi pregleda kliničnih študij, so vse potrdile neinferiornost novih antibiotikov v primerjavi s standardno terapijo, v določenih primerih pa celo njihovo superiornost ob ugodnem varnostnem profilu. Analiza toksikoloških parametrov je pokazala, da je tveganje za hepatotoksičnost nizko pri zoliflodacinu in gepotidacinu, slednji pa skupaj z lefamulinom izkazuje tudi manjši vpliv na kalijeve kanalčke, medtem ko za preostale učinkovine podatki v literaturi niso bili dostopni. Med preučevanimi interakcijami izstopa lefamulin kot najmočnejši zaviralec izoencima P450 3A4, kar zahteva previdnost pri njegovi sočasni uporabi z zdravili, ki se presnavljajo preko te poti. Namen te magistrske naloge je bil, da sistematično združimo podatke o klinični učinkovitosti in in silico ocene interakcij antibiotikov z novim mehanizmom delovanja.

• Jezik: Slovenski jezik
• Ključne besede: bakterijska rezistenca, zoliflodacin, gepotidacin, lefamulin, rifasutenizol, varnost, učinkovitost
• Vrsta gradiva: Magistrsko delo/naloga
• Tipologija: 2.09 - Magistrsko delo
• Organizacija: FFA - Fakulteta za farmacijo
• Založnik: [N. Kroflič]
• Leto izida: 2026
• PID: 20.500.12556/RUL-189733
• UDK: 615.2:543.645.7(043.2)
• COBISS.SI-ID: 300971267
• Datum objave v RUL: 14.10.2026

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Comparative analysis of the physicochemical properties, spectrum of activity, and efficacy of antibacterial agents

Izvleček

Bacterial antibiotic resistance represents a major global public health threat. Its most common causes include spontaneous genetic mutations, the widespread and often inappropriate use of antibiotics in human medicine, and their extensive application in livestock production. Resistance manifests as a reduced susceptibility or complete insensitivity of bacteria to antibacterial agents, ultimately leading to treatment failure. In this master’s thesis we focused on antibiotics with innovative mechanism of action that were either in phase II or III clinical development or had been approved between 2020 and 2025. The aim of the thesis was to provide a critical review of clinical studies for four selected drugs (zoliflodacin, gepotidacin, lefamulin and rifasutenizol). We evaluated their safety, efficacy and potential for drug-drug interactions and compared their physicochemical properties with those of already established antibiotics. The literature search was conducted in freely accessible databases, with MEDLINE serving as the main source of literature. Data on the affinity of the selected drugs for cytochrome P450 enzymes were obtained from ChEMBL. Their effects on safety-related targets were assessed by evaluating their affinity for potassium channels and their activity in the HepG2 cell line, as indicators of the risk of QT prolongation and hepatotoxicity, respectively. Based on the review of clinical studies, we confirmed the non-inferiority of the new antibacterial agents compared with established therapies. The analysis of toxicological parameters indicated a low risk of hepatotoxicity for zoliflodacin and gepotidacin. Gepotidacin, together with lefamulin, also showed a limited effect on potassium channels, suggesting a low to moderate risk for QT prolongation. Among the evaluated drugs, lefamulin was identified as the strongest CYP3A4 inhibitor, which suggests that caution is needed when it is co-administered with other drugs metabolized through this pathway. The aim of this master’s thesis was to systematically compile data on the clinical efficacy and in silico assessments of interactions of antibiotics with a novel mechanism of action.

• Ključne besede: bacterial resistance, zoliflodacin, gepotidacin, lefamulin, rifasutenizol, safety, efficacy