Natural biocide cocktails: Combinatorial antibiotic effects of prodigiosin and biosurfactants

Abstract

Bacterial secondary metabolites are naturally produced to prevail amongst competitors in a shared habitat and thus represent a valuable source for antibiotic discovery. The transformation of newly discovered antibiotic compounds into effective drugs often requires additional surfactant components for drug formulation. Nature may also provide blueprints in this respect: A cocktail of two compounds consisting of the antibacterial red pigment prodigiosin and the biosurfactant serrawettin W1 is naturally produced by the bacterium Serratia marcescens, which occurs in highly competitive habitats including soil. We show here a combinatorial antibacterial effect of these compounds, but also of prodigiosin mixed with other (bio)surfactants, against the soil-dwelling bacterium Corynebacterium glutamicum taken as a model target bacterium. Prodigiosin exerted a combinatorial inhibitory effect with all tested surfactants in a disk diffusion assay which was especially pronounced in combination with N-myristoyltyrosine. Minimal inhibitory and bactericidal concentrations (MIC and MBC) of the individual compounds were 2.56 μg/mL prodigiosin and 32 μg/mL N-myristoyltyrosine, and the MIC of prodigiosin was decreased by 3 orders of magnitude to 0.005 μg/mL in the presence of 16 μg/mL N-myristoyltyrosine, indicative of synergistic interaction. Investigation of bacterial survival revealed similar combinatorial effects; moreover, antagonistic effects were observed at higher compound concentrations. Finally, the investigation of microcolony formation under combined application of concentrations just below the MBC revealed heterogeneity of responses with cell death or delayed growth. In summary, this study describes the combinatorial antibacterial effects of microbial biomolecules, which may have ecological relevance by inhibiting cohabiting species, but shall furthermore inspire drug development in the combat of infectious disease.

Microfluidic systems for rapid antibiotic susceptibility tests (ASTs) at the single-cell level

“…73 To rapidly test the performance of these newly identied drug candidates, the high throughput microuidic systems show great potential. 74,75 The single-cell AST also holds huge potential for high throughput single bacterial heterogeneity analysis. 76 Since the antimicrobial susceptibility may differ among individual cells, the adequate detection of single bacterial heterogeneity is of great clinical importance.…”

Biologically active pigment and ShlA cytolysin of Serratia marcescens induce autophagy in a human ocular surface cell line

“…Our genetic and biochemical results indicate that prodigiosin can activate autophagy in the tested human corneal cell line. Prodigiosin, 2-methyl-3-pentyl-6-methoxyprodiginine, is thought to contribute to bacterial competition, and has antitumor capabilities [37,40,41]. Furthermore, prodigiosin was recently shown to activate autophagic cell death in a variety of cancer cell lines and to reduce tumor proliferation in mouse tracheas [42][43][44][45][46][47][48][49].…”

Dynamic Environmental Control in Microfluidic Single‐Cell Cultivations: From Concepts to Applications

“…This method is often used when single medium changes are performed. Applications range from changes in carbon sources [ 71,72 ] to studies with potential effectors such as antibiotics. [ 72–74 ] Although this method is quite simple in handling, the implementation of oscillating conditions and defined pulses is hardly possible.…”

“…Applications range from changes in carbon sources [ 71,72 ] to studies with potential effectors such as antibiotics. [ 72–74 ] Although this method is quite simple in handling, the implementation of oscillating conditions and defined pulses is hardly possible. Furthermore, the manual interruption of live‐cell experiments bears the risk to disturb experimental conditions for example through air, contaminations, etc.…”