A Challenging View: Antibiotics Play a Role in the Regulation of the Energetic Metabolism of the Producing Bacteria

Abstract

Antibiotics are often considered as weapons conferring a competitive advantage to their producers in their ecological niche. However, since these molecules are produced in specific environmental conditions, notably phosphate limitation that triggers a specific metabolic state, they are likely to play important roles in the physiology of the producing bacteria that have been overlooked. Our recent experimental data as well as careful analysis of the scientific literature led us to propose that, in conditions of moderate to severe phosphate limitation—conditions known to generate energetic stress—antibiotics play crucial roles in the regulation of the energetic metabolism of the producing bacteria. A novel classification of antibiotics into types I, II, and III, based on the nature of the targets of these molecules and on their impact on the cellular physiology, is proposed. Type I antibiotics are known to target cellular membranes, inducing energy spilling and cell lysis of a fraction of the population to provide nutrients, and especially phosphate, to the surviving population. Type II antibiotics inhibit respiration through different strategies, to reduce ATP generation in conditions of low phosphate availability. Lastly, Type III antibiotics that are known to inhibit ATP consuming anabolic processes contribute to ATP saving in conditions of phosphate starvation.

Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

“…However, things might not be as simple as described above, since the biosynthesis of bioactive molecules is usually triggered by some specific physiological or environmental conditions, often linked to nutritional limitation and growth slowdown [12,35], and these molecules are believed to fulfill important regulatory roles for the producing bacteria in such contexts [12]. For instance, S. coelicolor, a strain characterized by an active oxidative metabolism consuming acetylCoA and thus bearing a low lipid content, produces antibiotics proposed to contribute to the regulation of its energetic metabolism [12]. Our data suggested that the existence of a negative correlation between lipid content and antibiotic activity, previously established for S. coelicolor, was also true for most Streptomyces strains, at least on R2YE glucose.…”

“…The biosynthesis of such antibiotics is thus expected to be reduced on glycerol. Antibiotics of this class (defined as class II in Virolle, 2020 [12]) are thought to have anti-oxidant functions via their ability to capture electrons from the respiratory chain to prevent the formation of ROS or NOS, but in doing so, they would also be inhibitory to respiration and thus toxic for living cells.…”

“…In eukaryotes, antimycin impairs the correct functioning of the cytochrome c reductase, a key mitochondrial enzyme of the respiratory chain, and thus inhibits oxidative phosphorylation [26,27] Streptomyces is known to possess several cytochrome c reductases/oxidases that could possibly be antimycin targets, but no report in the literature indicates that antimycin has an impact on the respiratory activity of Streptomyces producing strains. However, we think that it is likely that antimycin plays such a role in the producing strain since bio-active molecules often fulfill transient but important regulatory roles in their producer [12]. Furthermore, Streptomyces genomes are known to encode several eukaryotic-like enzymes as well as biosynthetic pathways directing the synthesis of molecules regulating their activity as well as that of their eukaryotic orthologs [28][29][30].…”

“…The activation of the oxidative metabolism of these strains was shown to be correlated with the production of the antibiotics CDA (calcium dependent antibiotic), RED (undecylprodigiosin) and ACT (actinorhoddin) [7]. CDA and RED were proposed to create damage to the membrane, contributing to the cell death and lysis of a fraction of the population [7,12,13]. This would provide nutrients, and especially phosphate, to support the activation of the oxidative metabolism of the surviving population.…”

“…), was proposed to act as an electron acceptor [7]. In a context of low phosphate availability, ACT would reduce the electron flow through the respiratory chain, reducing respiration efficiency and thus ATP generation, in order to adjust it to low phosphate availability [7,12].…”