AI Article Synopsis
- Second messenger molecules like Ap4A are crucial for how cells react to stress, especially when dealing with harmful substances like aminoglycoside antibiotics.
- The study reveals that high levels of these antibiotics lead to increased production of Ap4A in bacteria, enhancing their sensitivity to antibiotic-induced cell death.
- Manipulating Ap4A levels, either by inhibiting its breakdown or boosting its production, could improve the effectiveness of aminoglycosides, potentially allowing lower, safer doses to treat drug-resistant infections.
Article Abstract
Second messenger molecules play important roles in the responses to various stimuli that can determine a cell's fate under stress conditions. Here, we report that lethal concentrations of aminoglycoside antibiotics result in the production of a dinucleotide alarmone metabolite-diadenosine tetraphosphate (Ap4A), which promotes bacterial cell killing by this class of antibiotics. We show that the treatment of with lethal concentrations of kanamycin (Kan) dramatically increases the production of Ap4A. This elevation of Ap4A is dependent on the production of a hydroxyl radical and involves the induction of the Ap4A synthetase lysyl-tRNA synthetase (LysU). Ectopic alteration of intracellular Ap4A concentration via the elimination of the Ap4A phosphatase diadenosine tetraphosphatase (ApaH) and the overexpression of LysU causes over a 5,000-fold increase in bacterial killing by aminoglycosides. This increased susceptibility to aminoglycosides correlates with bacterial membrane disruption. Our findings provide a role for the alarmone Ap4A and suggest that blocking Ap4A degradation or increasing its synthesis might constitute an approach to enhance aminoglycoside killing potency by broadening their therapeutic index and thereby allowing lower nontoxic dosages of these antibiotics to be used in the treatment of multidrug-resistant infections.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511005 | PMC |
| http://dx.doi.org/10.1073/pnas.1822026116 | DOI Listing |
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