Targeting the molecular chaperone SlyD to inhibit bacterial growth with a small molecule.
Molecular chaperones are essential molecules for cell growth, whereby they maintain protein homeostasis. Because of their central cellular function, bacterial chaperones might be potential candidates for drug targets. Antimicrobial resistance is currently one of the greatest threats to human health, with gram-negative bacteria being of major concern. We found that a Cu2+complex readily crosses the bacterial cell wall and inhibits SlyD, which is a molecular chaperone, cis/trans peptidyl prolyl isomerise (PPIase) and involved in various other metabolic pathways. The Cu2+complex binds to the active sites of SlyD, which suppresses its PPIase and chaperone activities. Significant cell growth retardation could be observed for pathogenic bacteria (e.g., Staphylococcus aureus and Pseudomonas aeruginosa). We anticipate that rational development of drugs targeting molecular chaperones might help in future control of pathogenic bacterial growth, in an era of rapidly increasing antibiotic resistance.
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.|Institute of Physics, Biophysics, Martin Luther University, Halle, Wittenberg, Germany.
Amit
A
Kumar
Institute of Physics, Biophysics, Martin Luther University, Halle, Wittenberg, Germany.|Centre for Structure und Dynamics of Proteins (MZP), Martin Luther University Halle, Wittenberg, Germany.
Jochen
J
Balbach
D000873:Anthracenes / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D016503:Drug Delivery Systems; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008826:Microbial Sensitivity Tests; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D011725:Pyridines / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics
D000873:Anthracenes; D000900:Anti-Bacterial Agents; D056831:Coordination Complexes; D029968:Escherichia coli Proteins; D011725:Pyridines; C085606:SlyD protein, E coli; D003300:Copper; D019696:Peptidylprolyl Isomerase