Targeting the molecular chaperone SlyD to inhibit bacterial growth with a small molecule

Abstract

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.

Fermentation products in the cystic fibrosis airways induce aggregation and dormancy-associated expression profiles in a CF clinical isolate of Pseudomonas aeruginosa

“…This further supports our hypothesis that exposure to lactic acid and 2,3-butanediol alter physiology in clinically relevant ways. In particular, a down-regulated gene slyD , a molecular chaperone, is a key molecule involved in cell growth (Kumar and Balbach 2017 ). Additionally, fklB , a gene that has been shown to increase susceptibility of P. aeruginosa to B-lactams when mutated is also down-regulated (Alvarez-Ortega et al.…”

A Cu2+ complex induces the aggregation of human papillomavirus oncoprotein E6 and stabilizes p53

“…4H,I), while residues Met1-Gln6, Lys11, Gln14, His24, Tyr43 and Leu100 remain almost unaffected. NMR intensities decreased for those residues, which are in close proximity to the paramagnetic Cu 2+ moiety, because of paramagnetic relaxation enhancement [19,29].…”

A small-molecule acts as a ‘roadblock’ on DNA, hampering its fundamental processes

“…-Zn 2+ complex interacted with the grooves of DNA -Zn 2+ There is a continuous effort to develop small molecules, including metal-based coordination complexes, for oncotherapy as well as novel anti-microbial agents [5][6][7][8].…”

“…Many of the currently developed coordination complexes exhibited cytotoxicity under in vitro conditions with either an apoptotic mode of action, or more often with an unknown mechanism, without knowing their cellular targets [12]. However, it is of medical interest to find coordination complexes/small molecules which are able to cross the cell wall/membrane barrier and exhibit cell toxicity by targeting the biomolecules responsible for specific housekeeping pathways [5,13].…”

“…Next, the significance of roadblock activity was analysed against the pathogenic bacteria Staphylococcus aureus (gram-positive) and Pseudomonas aeruginosa (gram-negative) as chosen from the 'ESKAPE pathogens' category [5,16,31]. The IC50 was found to be 9.0 ± 0.2 µM and 8.65 ± 0.7 µM for Staphylococcus aureus and Pseudomonas aeruginosa, respectively ( Figure 6).…”