Avtor/Urednik		Sosič, Izidor; Turk, Samo; Sinreih, Maša; Trošt, Nuša; Verlaine, Olivier; Amoroso, Ana; Zervosen, Astrid; Luxen, André; Joris, Bernard; Gobec, Stanislav
Naslov		Exploration of the chemical space of novel naphthalene-sulfo namide and anthranilic acid-based inhibitors of penicillin-binding proteins
Tip		članek
Vir		Acta Chim Slov
Vol. in št.		Letnik 59, št. 2
Leto izdaje		2012
Obseg		str. 380-8
Jezik		eng
Abstrakt		Penicillin-binding proteins are a well established, validated and still a very promising target for the design and development of new antibacterial agents. Based on our previous discovery of several noncovalent small-molecule inhibitor hits for resistant PBPs we decided to additionally explore the chemical space around these compounds. In order to clarify their structure-activity relationships for PBP inhibition two new series of compounds were synthesized, characterized and evaluated biochemically: the derivatives of anthranilic acid and naphthalene-sulfonamide derivatives. The target compounds were tested for their inhibitory activities on three different transpeptidases: PBP2a from methicillin-resistant Staphylococcus aureus (MRSA) strains, PBP5fm from Enterococcus faecium strains, and PBP1b from Streptococcus pneumoniae strains. The most promising results for both of these series of compounds were obtained against the PBP2a enzyme with the IC50 values in the micromolar range. Although these results do not represent a significant breakthrough in the field of noncovalent PBP inhibitors, they do provide useful structure-activity relationship data, and thus a more solid basis for the design of potent and noncovalent inhibitors of resistant PBPs.
Izvleček		Penicilin vezoči proteini (PBP) so uveljavljena, validirana ter še vedno obetavna tarča za načrtovanje in razvoj novih protimikrobnih učinkovin. Na osnovi naših, pred kratkim odkritih nekovalentnih inhibitorjev (zadetkov) PBP iz rezistentnih sevov smo se odločili dodatno raziskati kemijski prostor teh spojin. Z namenom dodobra razjasniti odnos med strukturo in delovanjem smo sintetizirali ter biokemijsko ovrednotili dve seriji spojin: derivate antranilne kisline ter naftalen- sulfonamidne derivate. Spojinam smo določili inhibitorno aktivnost na treh različnih transpeptidazah, in sicer na PBP2a iz na meticilin odpornega Staphylococcus aureus (MRSA), PBP5fm iz Enterococcus faecium (sev D63r) ter na PBP1b iz seva Streptococcus pneumoniae. Najbolj obetavne rezultate pri obeh serijah spojin smo dobili na encimu PBP2a z IC50 vrednostmi v mikromolarnem območju. Čeprav ti rezultati ne predstavljajo signifikantnega preboja na področju nekovalentnih inhibitorjev PBP, pa zagotovo nudijo uporabne podatke o odnosu med strukturo in delovanjem ter tako tudi boljšo osnovo za nadaljnje načrtovanje močnih, nekovalentnih inhibitorjev PBP iz rezistentnih bakterij.