The anti-virulence activity of the non-mevalonate pathway inhibitor FR900098 towards is maintained during experimental evolution.

infections are difficult to treat and there is an urgent need for alternative (combination) treatments. The use of anti-virulence therapies in combination with antibiotics is a possible strategy to increase the antimicrobial susceptibility of the pathogen and to slow down the development of resistance. In the present study we evaluated the β-lactam and colistin-potentiating activity, and anti-virulence effect of the non-mevalonate pathway inhibitor FR900098 against in various and models. In addition, we evaluated whether repeated exposure to FR900098 alone or when combined with ceftazidime leads to increased resistance. FR900098 potentiated the activity of colistin and several β-lactam antibiotics (aztreonam, cefepime, cefotaxime, ceftazidime, mecillinam and piperacillin) but not of imipenem and meropenem. When used alone or in combination with ceftazidime, FR900098 increased the survival of infected and . Furthermore, combining ceftazidime with FR900098 resulted in a significant inhibition of the biofilm formation of . Repeated exposure to FR900098 in the infection model did not lead to decreased activity, and the susceptibility of the evolved HI2424 lineages to ceftazidime, FR900098 and the combination of both remained unchanged. In conclusion, FR900098 reduces virulence and potentiates ceftazidime in an model, and this activity is not lost during the experimental evolution experiment carried out in the present study.