Določanje protibakterijskega spektra delovanja zaviralcev DNA giraze

Ažbe, Nika (author), Pajk, Stane (mentor), Hrast, Martina (co-mentor)

Protibakterijske učinkovine uporabljamo za zdravljene bakterijskih okužb. Ker se bakterije hitro prilagodijo na protibakterijske učinkovine in razvijejo odpornost, predstavlja boj proti odpornim bakterijam velik izziv. Staphylococcus pseudintermedius je bakterija, ki jo najdemo na koži in sluznici psov in povzroča različne bolezni. Zdravljenje okužb s sevi bakterije Staphylococcus pseudintermedius, ki so odporni na meticilin postaja velik problem v veterinarski medicini. Pomembna tarča za odkrivanje novih protibakterijskih učinkovin je esencialni bakterijski encim DNA giraza, ki je sestavljena iz dveh podenot giraze A (GyrA) in iz dveh podenot DNA giraze B (GyrB). Poznamo zaviralce podenote GyrA (kinoloni, novi zaviralci bakterijske topoizomeraze) in zaviralce podenote GyrB. Strukturo novih zaviralcev bakterijske topoizomeraze lahko razdelimo na tri dele: heteroaromatski biciklični levi del, distančnik in aromatski heterociklični desni del. V okviru magistrske naloge smo ovrednotili protibakterijsko aktivnost spojin zaviralcev DNA giraze. Občutljivost mikroorganizmov na protimikrobne učinkovine smo opisali z minimalno inhibitorno koncentracijo (MIK). Testirali smo 30 spojin novih zaviralcev bakterijske topoizomeraze, ki se razlikujejo v aromatskem heterocikličnem desnem delu, in 6 spojin zaviralcev podenote GyrB. Protibakterijsko aktivnost smo vsem spojinam določili na 15 sevov na meticilin odporni Staphylococcus pseudintermedius, novim zaviralcem bakterijske topoizomeraze pa še na druge izbrane G+ in G- bakterije. Kot najboljši zaviralci z najnižjimi vrednostmi minimalne inhibitorne koncentracije so se izkazale p-halogenirane spojine ter monofluorirani in difluorirani analogi. Zaviralci podenote GyrB pri katerih smo protibakterijsko aktivnost testirali samo na meticilin odporni Staphylococcus pseudintermedius sevih, izkazujejo dobre protibakterijske lastnosti proti vsem sevom na meticilin odporni Staphylococcus pseudintermedius. Testirane spojine močneje zavirajo G+ bakterije, nekatere izkazujejo aktivnost tudi proti G- bakterijam, vendar je ta slabša. Veliko testiranih spojin ima močnejše delovanje kot tetraciklin, ki je bil uporabljan kot pozitivna kontrola.

• Language: Slovenian
• Keywords: protibakterijske učinkovine, novi zaviralci bakterijske DNA giraze, DNA giraza, na meticilin odporen Staphylococcus pseudintermedius, minimalna inhibitorna koncentracija
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-135960
• Publication date in RUL: 05.04.2022

Secondary language

• Language: English
• Title: Determination of DNA gyrase inhibitors’ antibacterial activity spectrum

Abstract

We use antibacterial agents to treat bacterial infections. Fighting resistant bacteria is a major challenge because bacteria quickly adapt to antibacterial agents and develop resistance. Staphylococcus pseudintermedius is a bacterium found on the skin and mucous membranes of dogs and it can cause various diseases. The treatment of infections with methicillin-resistant strains of Staphylococcus pseudintermedius is becoming a major problem in veterinary medicine. Essential bacterial enzyme DNA gyrase is an important target for new antibacterial agents. DNA gyrase consists of two gyrase A subunits (GyrA) and two DNA gyrase B subunits (GyrB). We know GyrA subunit inhibitors (quinolones, new bacterial topoisomerase inhibitors) and GyrB subunit inhibitors. The structure of NBTI can be divided into three parts: heteroaromatic bicyclic left part, spacer and aromatic heterocyclic right part. As part of the master's thesis, we evaluated the antibacterial activity of DNA gyrase inhibitors. The susceptibility of microorganisms to antimicrobial agents was described with a minimum inhibitory concentration (MIC). We tested 30 new bacterial topoisomerase inhibitors that are different in the aromatic heterocyclic right part and 6 GyrB subunit inhibitor compounds. Antibacterial activity was determined for all compounds on 15 methicillin-resistant Staphylococcus pseudintermedius strains, and for new bacterial topoisomerase inhibitors on other selected G + and G-bacteria. P-halogenated compounds and monofluorinated and difluorinated analogues proved to be the best inhibitors with the lowest MIC values. GyrB subunit inhibitors in which antibacterial activity was tested only on methicillin-resistant strains of Staphylococcus pseudintermedius, have good antibacterial properties against all methicillin-resistant of Staphylococcus pseudintermedius strains. The tested compounds inhibit G+ bacteria more strongly, some also show activity against G-bacteria, but not as strong as the activity against G+ bacteria. Many of the compounds tested, however, have a stronger action than tetracycline, which was used as a positive control.

• Keywords: antibacterial agents, novel bacterial topoisomerase inhibitors, DNA gyrase, methicillin-resistant strains of Staphylococcus pseudintermedius, minimum inhibitory concentration