(p)ppGpp is at the core of global bacterial regulation as it controls growth, the most important aspect of life. It would therefore be expected that at least across a species the intrinsic (basal) levels of (p)ppGpp would be reasonably constant. On the other hand, the historical contingency driven by the selective pressures on bacterial populations vary widely resulting in broad genetic polymorphism. Given that (p)ppGpp controls the expression of many genes including those involved in the bacterial response to environmental challenges, it is not surprising that the intrinsic levels of (p)ppGpp would also vary considerably. In fact, null mutations or less severe genetic polymorphisms in genes associated with (p)ppGpp synthesis and hydrolysis are common. Such variation can be observed in laboratory strains, in natural isolates as well as in evolution experiments. High (p)ppGpp levels result in low growth rate and high tolerance to environmental stresses. Other aspects such as virulence and antimicrobial resistance are also influenced by the intrinsic levels of (p)ppGpp. A case in point is the production of Shiga toxin by certain E. coli strains which is inversely correlated to (p)ppGpp basal level. Conversely, (p)ppGpp concentration is positively correlated to increased tolerance to different antibiotics such as β-lactams, vancomycin, and others. Here we review the variations in intrinsic (p)ppGpp levels and its consequences across the E. coli species.

Glyphosate is a herbicide widely used in food production that blocks the synthesis of aromatic amino acids in plants and in microorganisms and also induces the accumulation of the alarmone (p)ppGpp. Resistance, tolerance and persistence to antibiotics are common phenomena that contribute to antibiotic treatment failure. There are several mechanisms through which bacteria attain tolerance or persistence to antibiotics, but all of them involve partial or complete growth inhibition. In this study we evaluated the effect of glyphosate on the resistance, tolerance, and persistence towards the antibiotics ampicillin, ciprofloxacin and kanamycin and the possible role of (p)ppGpp in this activity. Glyphosate did not affect the minimum inhibitory concentration of these antibiotics, but enhanced bacterial tolerance and/or persistence towards them. The upshift in ciprofloxacin and kanamycin tolerance was partially dependent on the presence of relA that promotes (p)ppGpp accumulation in response to glyphosate. Conversely, the strong increase in ampicillin tolerance caused by glyphosate was independent of relA. We conclude that by inducing aromatic amino acid starvation glyphosate contributes to the temporary increase in E. coli tolerance or persistence, but does not affect antibiotic resistance.

Glyphosate is a herbicide widely used in food production that blocks the synthesis of aromatic amino acids in plants and in microorganisms and also induces the accumulation of the alarmone (p)ppGpp. The purpose of this study was to investigate whether glyphosate affects the resistance, tolerance or persistence of bacteria towards three different classes of antibiotics and the possible role of (p)ppGpp in this activity. Glyphosate did not affect the minimum inhibitory concentration of the tested antibiotics, but enhanced bacterial tolerance and/or persistence towards them. The upshift in ciprofloxacin and kanamycin tolerance was partially dependent on the presence of relA that promotes (p)ppGpp accumulation in response to glyphosate. Conversely, the strong increase in ampicillin tolerance caused by glyphosate was independent of relA. We conclude that by inducing aromatic amino acid starvation glyphosate contributes to the temporary increase in E. coli tolerance or persistence, but does not affect antibiotic resistance.