Anionic fluoroquinolones as antibacterials against biofilm-producing Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is a common biofilm-forming bacterial pathogen implicated in diseases of the lungs. The extracellular polymeric substances (EPS) of respiratory Pseudomonas biofilms are largely comprised of anionic molecules such as rhamnolipids and alginate that promote a mucoid phenotype. In this Letter, we examine the ability of negatively-charged fluoroquinolones to transverse the EPS and inhibit the growth of mucoid P. aeruginosa. Anionic fluoroquinolones were further compared with standard antibiotics via a novel microdiffusion assay to evaluate drug penetration through pseudomonal alginate and respiratory mucus from a patient with cystic fibrosis.

Keywords: Antibacterial; Biofilm; Fluoroquinolone; Mucoid; Pseudomonas.

Figure 1

Structures of (a) rhamnolipids and (b) alginate in biofilm-producing Pseudomonas aeruginosa.

Figure 2

N-Protio fluoroquinolones and N-substituted derivatives 1-6.

Figure 3

N-Acyl fluoroquinolones 1d-1m.

Figure 4

Microdiffusion assay design.

Figure 5

Respiratory mucus and EPS of Pseudomonas biofilms reduce the bioavailability of inhaled and systemic antibiotics.

Scheme 1

Synthesis of carboxyfluoroquinlones 1n-1p.

Scheme 2

Synthesis of N-alkyl fluoroquinolones 1q-1w.