Enterobacterial Responses to External Protons, Including Responses That Involve Early Warning Against Stress and the Functioning of Extracellular Pheromones, Alarmones and Varisensors

Several striking findings, related to biological effects of external acidity, are reviewed here. The first of these relates to the role of PhoE in the penetration of H+ and protonated metabolites into the cell. PhoE is an anion pore and would not be expected to take up protons. The work reviewed here, however, shows that the loss or repression of PhoE leads to poor H+ passage through the outer membrane (OM), whilst derepression of PhoE leads to facilitated passage. It is now believed that H+ crosses through the PhoE pore in association possibly with oligopeptides, and that other protonated molecules, such as the acid tolerance EIC, use the same means to cross the OM. Additionally, several processes that form early warning systems against acidity are reviewed here. First, the properties of the acid tolerance EIC alarmones allow them to diffuse to regions not yet facing acid stress, and there give early warning and induce sensitive organisms to tolerance. Second, some agents, such as glucose, induce acid tolerance in organisms, long before these organisms are exposed to catabolically-produced acidity, preparing them, in advance, to resist this impending acid challenge. Third, the occurrence of multiple forms of ESCs (i.e. of varisensors) ensures that where organisms have been grown under conditions that sensitise them to acid stress, the ESCs formed are modified so as to be activated at much higher pH values, ensuring that lethality by acid is reduced or abolished. Fourthly, normally only EICs induce tolerance. Strikingly, however, pH 8.5 or 9.0-grown cells are induced to tolerance by ESC formed at pH 6.5. This is believed to provide another early warning system, protecting alkali-grown cells against sudden acidification of media. Two other finding reviewed here should be emphasised. First, the hydrophobic antibiotic novobiocin is ineffective against enterobacteria, due to its failure to penetrate the OM barrier. This only applies to cultures in pH 7.0 media, however, cells growing at pH 5.0 being exquisitely sensitive to novobiocin, due to a conformational change to the antibiotic at acidic pH, which allows ready penetration through the OM. Second, acidic pHs affect the synthesis and effects of another antibiotic, namely colicin V. Thus pH 5.0 prevents both synthesis of this agent and its effects on sensitive cells. Exposure to external acidity leads to numerous other effects, including those that influence growth, cell division, plasmid transfer and chemotaxis; these have also been reviewed here.