To understand the robustness of combination inhibitor therapies across diverse bacterial species, we test each strategy against a number of biochemical and transcriptional variants of the experimentally validated QS model. We find that a combination of LuxI and LuxR non-competitive inhibitors act multiplicatively to inhibit virulence for a broad range of QS systems. In contrast, we find that LuxR competitive inhibitors act antagonistically with LuxI inhibitors, due to the weak activation of LuxR; in some conditions this can actually increase virulence. Both these results are somewhat surprising, and seem to arise due to the global structure of QS systems. Combination therapies must therefore be used with care, only once the most relevant drug combinations and molecular targets have been identified for each pathogenic species and infection context. QS inhibitors are promising alternatives to antibiotics, but there are still many steps on the path to their widespread use. It has been argued that pathogens targeted with QS inhibitors would be under weaker selective pressure to develop resistance, compared to the MLN4924 pressures induced by antibiotics. However, the reality is more complex: in an infection context, individuals resistant to QS inhibition have a major advantage, and tend to be selected. Combination drug therapies that target multiple molecules simultaneously would lower the rate at which such resistant 
individuals spontaneously arose. This motivated us to ask which QS targets would respond best to simultaneous inhibition. QS being implemented by a non-linear feedback system, the answer to such a question is far from obvious: it will vary from one pathogen to another, depending on the underlying feedback Fingolimod topology and biochemical parameter values. However, our analysis does produce some robust results. We find that a combination of LuxI inhibitors and LuxR noncompetitive inhibitors has the greatest capacity to suppress virulence, across a wide range of parameters. This strategy should be considered as the default: it can be applied without detailed knowledge of the pathogen��s QS system; moreover, since it targets two distinct molecules, the likelihood of spontaneous resistance is reduced. In contrast, LuxR competitive inhibitors should be used with care. These molecules tend to be AHL analogues with some weak capacity to activate LuxR. Though this capacity is much less than that of AHL itself when measured per molecule, the overall effect depends sensitively on AHL levels at the site of infection. Since physiological AHL concentrations tend to be low, competitive inhibitors in the form of AHL analogues can paradoxically increase virulence gene expression. Recently, structure-function studies have been used to design AHL analogues that completely block LuxR-DNA binding. Such studies show that LuxR competitive inhibitors might yet find use. New experiments can help improve the design of anti-virulence therapies at three levels. First: Any mathematical model such as ours is limited by the accuracy of the equations used, and of the parameter values they contain. Careful biochemical measurements can improve the predictive power of these models. Second: no mathematical model can account for the complications of realworld therapy. The true test of any strategy can only come from experimental studies on animal models, and ultimately from clinical trials. Third: our results should be understood in the context of a wider range of strategies, including the use of QS inhibitors in combination with antibiotics, as well as the stimulation of the host immune system. Research on pathogen biology will add to this list, revealing new and unexpected strategies.