Unconventional Antibacterials and Adjuvants

The need for new classes of antibacterials is genuine in light the dearth clinical options treatment bacterial infections. prodigious discoveries antibiotics during 1940s to 1970s, a period wistfully referred as Golden Age Antibiotics, have not kept up face emergence resistant bacteria past few decades. There has been renewed interest old drugs, repurposing existing and pairing synergistic or an antibiotic with adjuvant. Notwithstanding, novel these life-saving drugs become increasingly difficult, calling paradigms. We describe, herein, three strategies from our laboratories toward adjuvants using computational multidisciplinary experimental methods. One approach targets penicillin-binding proteins (PBPs), biosynthetic enzymes cell-wall peptidoglycan, non-?-lactam inhibitors. Oxadiazoles quinazolinones emerged two structural out efforts. Several hundred analogs synthesized fully characterized laboratories. A second ventures into inhibition allosteric regulation biosynthesis. mechanistic details PBP2a Staphylococcus aureus, discovered laboratories, outlined. site this protein at 60 distance active site, whereby ligand binding former makes access latter by substrate possible. documented that both ceftaroline, fifth-generation cephalosporin, bind manifestation antibacterial activity. Attempts regulatory phosphorylation events identified one class antibacterials, picolinamides. chemical structures hits went through diversification synthesis hundreds analogs. These were various assays identification leads adjuvant activities. Furthermore, we revisited mechanism bulgecins, abandoned 1980s. compounds potentiate activities ?-lactam formation bulges sites septum replication, which are points weakness envelope. experience rupture, death. Bulgecin inhibits lytic transglycosylase Slt Pseudomonas aeruginosa likely transition-state mimetic its turnover peptidoglycan. Once damage cell wall inflicted antibiotic, function repair damage. When inhibited bulgecin A, organism cannot cope it would undergo rapid lysis. effective antibiotics. small-molecule hold promise