title: Novel antibiotics targeting respiratory ATP synthesis in Gram-positive pathogenic bacteria.
abstract: Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens.
authors.affiliation: Department of Antimicrobial Research, Janssen Infectious Diseases and Diagnostics BVBA, Johnson & Johnson, Turnhoutseweg, Beerse, Belgium.
authors.forename: Wendy
authors.initials: W
authors.lastname: Balemans
authors.forename: Luc
authors.initials: L
authors.lastname: Vranckx
authors.forename: Nacer
authors.initials: N
authors.lastname: Lounis
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Pop
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guillemont
authors.forename: Karen
authors.initials: K
authors.lastname: Vergauwen
authors.forename: Selena
authors.initials: S
authors.lastname: Mol
authors.forename: Ron
authors.initials: R
authors.lastname: Gilissen
authors.forename: Magali
authors.initials: M
authors.lastname: Motte
authors.forename: David
authors.initials: D
authors.lastname: Lançois
authors.forename: Miguel
authors.initials: M
authors.lastname: De Bolle
authors.forename: Kristien
authors.initials: K
authors.lastname: Bonroy
authors.forename: Holger
authors.initials: H
authors.lastname: Lill
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Dirk
authors.initials: D
authors.lastname: Bald
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
mesh_terms: D025181:ATP Synthetase Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D045744:Cell Line, Tumor; D024881:Drug Resistance, Bacterial / Q000235:genetics; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000254:growth & development; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D011804:Quinolines; D000255:Adenosine Triphosphate; D025181:ATP Synthetase Complexes