Extreme Acid Modulates Fitness Trade-Offs of Multidrug Efflux Pumps MdtEF-TolC and AcrAB-TolC in Escherichia coli K-12.

Bacterial genomes encode various multidrug efflux pumps (MDR) whose specific conditions for fitness advantage are unknown. We show that the efflux pump MdtEF-TolC, in Escherichia coli, confers a fitness advantage during exposure to extreme acid (pH 2). Our flow cytometry method revealed pH-dependent fitness trade-offs between bile acids (a major pump substrate) and salicylic acid, a membrane-permeant aromatic acid that induces a drug resistance regulon but depletes proton motive force (PMF). The PMF drives MdtEF-TolC and related pumps such as AcrAB-TolC. Deletion of mdtE (with loss of the pump MdtEF-TolC) increased the strain's relative fitness during growth with or without salicylate or bile acids. However, when the growth cycle included a 2-h incubation at pH 2 (below the pH growth range), MdtEF-TolC conferred a fitness advantage. The fitness advantage required bile salts but was decreased by the presence of salicylate, whose uptake is amplified by acid. For comparison, AcrAB-TolC, the primary efflux pump for bile acids, conferred a PMF-dependent fitness advantage with or without acid exposure in the growth cycle. A different MDR pump, EmrAB-TolC, conferred no selective benefit during growth in the presence of bile acids. Without bile acids, all three MDR pumps incurred a large fitness cost with salicylate when exposed at pH 2. These results are consistent with the increased uptake of salicylate at low pH. Overall, we showed that MdtEF-TolC is an MDR pump adapted for transient extreme-acid exposure and that low pH amplifies the salicylate-dependent fitness cost for drug pumps. IMPORTANCE Antibiotics and other drugs that reach the gut must pass through stomach acid. However, little is known of how extreme acid modulates the effect of drugs on gut bacteria. We find that extreme-acid exposure leads to a fitness advantage for a multidrug pump that otherwise incurs a fitness cost. At the same time, extreme acid amplifies the effect of salicylate selection against multidrug pumps. Thus, organic acids and stomach acid could play important roles in regulating multidrug resistance in the gut microbiome. Our flow cytometry assay provides a way to measure the fitness effects of extreme-acid exposure to various membrane-soluble organic acids, including plant-derived nutrients and pharmaceutical agents. Therapeutic acids might be devised to control the prevalence of multidrug pumps in environmental and host-associated habitats.

EU-Asian-American Partnership for a Third Industrial Revolution: Transitioning to High Productivity, Sustainable Infrastructures in the Age of COVID-19.

The COVID-19 virus has caused a crisis for the world's economy and markets. The World Health Organization has declared the virus to be a global pandemic, meaning that it will have a sustained impact worldwide. In response to the shutdown of economies, governments across the world have implemented fiscal and monetary stimulus packages to counteract the disruption caused by the coronavirus. However, with many countries' economies already slowing before the pandemic, the measures to combat the virus risk sending many countries into full scale recession for the first time since 2009, according to the European Commission. COVID-19 has demonstrated the vulnerability of global supply chains and the need for more resilient infrastructures. Yet Europe cannot do this alone. The EU can only achieve this by strengthening ties and increasing trade cooperation with Asia and South America, in alignment with the values of sustainability. Prior to the COVID-19 crisis, however, the EU has had major public disagreements around trade with both regions, essentially on environmental issues. By prioritising cooperation, the EU can work with developing countries in Asia and South America to take tangible steps towards environmentally sustainable production while boosting economic trade.