The intracellular bacterial pathogen Listeria monocytogenes activates a robust 
type I interferon response upon infection. This response is partially dependent 
on the multidrug resistance (MDR) transporter MdrM and relies on cyclic-di-AMP 
(c-di-AMP) secretion, yet the functions of MdrM and cyclic-di-AMP that lead to 
this response are unknown. Here we report that it is not MdrM alone but a cohort 
of MDR transporters that together contribute to type I interferon induction 
during infection. In a search for a physiological function of these 
transporters, we revealed that they play a role in cell wall stress responses. A 
mutant with deletion of four transporter genes (ΔmdrMTAC) was found to be 
sensitive to sublethal concentrations of vancomycin due to an inability to 
produce and shed peptidoglycan under this stress. Remarkably, c-di-AMP is 
involved in this phenotype, as overexpression of the c-di-AMP phosphodiesterase 
(PdeA) resulted in increased susceptibility of the ΔmdrMTAC mutant to 
vancomycin, whereas overexpression of the c-di-AMP diadenylate cyclase (DacA) 
reduced susceptibility to this drug. These observations suggest a physiological 
association between c-di-AMP and the MDR transporters and support the model that 
MDR transporters mediate c-di-AMP secretion to regulate peptidoglycan synthesis 
in response to cell wall stress.