Targeting bacterial persisters with small molecular probes

Microbial persistence has been found to be strictly correlated to chronic and recurrent infections, which represent an increasing economic burden for the worldwide society.[1] Persister cells[2] are a dormant bacterial phenotype, temporary resistant to antibiotic treatment. Acting on the signalling cascade that allows bacteria to activate this phenotypic switch should prevent the incomplete sterilization, that is often responsible of relapsing infections and somehow connected to the insurgence of specific antibiotic resistance.[3] The cellular levels of (p)ppGpp (Guanosine penta- or tetraphosphate), a widespread alarmone amongst bacterial species, has been postulated to be a trigger of the persistent phenotype[4] and, following this lead, we aim to investigate whether it is possible to prevent persiters formation by efficiently inhibiting (p)ppGpp synthesis. (p)ppGpp synthesis and degradation is catalysed by the RSH (RelA/SpoT Homologue) enzyme superfamily,[5] of which only the S. equisimilis isoform (RelSeq) has been structurally characterized.[6] So far, only a small group of (p)ppGpp analogues that perform as weak Rel inhibitors have been reported,[7] showing promising effects on sporulation and biofilm formation in B. subtilis.[8] Much work still needs to be done to obtain active and selective compounds and, in order to do so, we aim to target the synthethase site of RelSeq with rationally designed small molecular probes. A validated computational model of RelSeq has been obtained and the first results of virtual screening and probes design will be presented. References [1] E. Maisonneuve, K. Gerdes, Cell 2014, 157, 539-548. [2] K. Lewis, Annu. Rev. Microbiol. 2010, 64, 357-372. [3] J. Wu, Q. Long, J. Xie, J. Cell. Physiol. 2010, 224, 300-304. [4] V. Hauryliuk, G. C. Atkinson, K. S. Murakami, T. Tenson, K. Gerdes, Nat Rev Microbiol 2015, 13, 298-309. [5] G. C. Atkinson, T. Tenson, V. Hauryliuk, PLoS ONE 2011, 6, e23479. [6] T. Hogg, U. Mechold, H. Malke, M. Cashel, R. Hilgenfeld, Cell 2004, 117, 57-68. [7] E. Wexselblatt, I. Kaspy, G. Glaser, J. Katzhendler, E. Yavin, Eur J Med Chem 2013, 70, 497-504. [8] E. Wexselblatt, Y. Oppenheimer-Shaanan, I. Kaspy, N. London, O. Schueler-Furman, E. Yavin, G. Glaser, J. Katzhendler, S. Ben-Yehuda, PLoS Pathog 2012, 8, e1002925.