Palmitoyl‐dl‐Carnitine is a Multitarget Inhibitor of Pseudomonas aeruginosa Biofilm Development

Abstract

Bacteria growing in biofilms are often in metabolic and physiological states that do not respond well to antibiotics, and thus, are major contributors to chronic diseases. Biofilm inhibitors, therefore, have the potential to be used alone or as adjuvants to conventional antibiotic therapies. Here, we screened a chemically diverse collection of protein kinase inhibitors for molecules that perturb biofilm development. Among the inhibitory molecules identified, palmitoyl-DL-carnitine (pDLC) impaired Pseudomonas aeruginosa and Escherichia coli biofilm formation in a dose-dependent manner. The pDLC affected multiple pathways implicated in P. aeruginosa biofilm development; it stimulated motility, inhibited activity of the Las quorum sensing system, and overrode the biofilm-promoting effects of subminimal inhibitory concentrations of aminoglycosides and high levels of the second messenger, cyclic-di-GMP. Palmitic acid, but not carnitine, inhibited biofilm formation but did not stimulate motility, suggesting that pDLC works through unique mechanisms. The ability to target multiple pathways involved in biofilm formation is desirable in an inhibitor, which makes pDLC an interesting lead for antibiofilm therapies.

Small-Molecule Modulators of Listeria monocytogenes Biofilm Development

“…However, the effects of palmitoyl-D,Lcarnitine on biofilm formation are enantiomer independent, because the level of L. monocytogenes biofilm inhibition by all three compounds was similar. These data suggest that palmitoyl-D,Lcarnitine may impair biofilm development through multiple mechanisms, as was reported for its effects on P. aeruginosa (Wenderska et al [56]). …”

“…From our pilot screen of 80 kinase inhibitors, 19% reduced biofilm formation and 4% increased biofilm development, compared to Ͻ1% of stimulators and biofilm inhibitors that were identified from the screen of 66,095 compounds by Junker et al (24). In a recent screen of the same 80-compound collection using P. aeruginosa, Wenderska et al (56) found only two compounds (2.5%) that inhibited P. aeruginosa biofilm formation without affecting planktonic cell density. The differences in hit rates between screens may reflect the high density of known bioactives in the targeted kinase inhibitor library versus larger collections, and fewer efflux mechanisms in L. monocytogenes (19,31,42), compared to P. aeruginosa (29).…”

Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa

“…Antimicrobial Agents and Chemotherapy comparable to many previously reported antibiofilm compounds for P. aeruginosa (22,23,43). Since P. aeruginosa uses multiple matrix polymers (Pel, Psl, and eDNA) and adhesins (type IV pili, flagellum, among others) to attach and build a biofilm, compounds that repress EPS production will likely not be capable of complete biofilm repression.…”

Antibiotic resistance—the need for global solutions

“…Several eff orts to combine antibiotics with agents that prevent biofi lms from forming, disrupt them, or otherwise block their antibiotic insensitivity have been reported. 359,360 Some of these are quite potent in their eff ects in vitro, suggesting that the approach has merit for clinical assessment.…”