The BacA protein is playing an important role in the legume symbiosis of Sinorhizobium meliloti with alfalfa (Medicago sativa). The Mycobacterium tuberculosis ABC transporter homologue BacA was found to be important for the maintenance of chronic murine infections, yet its in vivo function is unknown. In the legume plant as well as in the mammalian host, bacteria encounter host antimicrobial peptides (AMPs). We found that the M. tuberculosis BacA protein was able to protect an S. meliloti BacA-deficient mutant from the antimicrobial activity of a synthetic legume peptide, NCR247 and a recombinant human ß-defensin 2 (HBD2). This finding was also confirmed using an M. tuberculosis insertional mutant. Furthermore, M. tuberculosis BacA-mediated protection of the legume symbiont S. meliloti against legume defensins as well as human ß-defensin 2 is dependent on its attached ATPase domain. In addition, we show that M. tuberculosis BacA is mediating peptide uptake of the truncated bovine AMP, Bac71-16. This process required a functional ATPase domain and a substrate binding protein. We therefore suggest that M. tuberculosis BacA is important for the transport of peptides across the cytoplamic membrane and is part of a complete ABC transporter. Hence, BacA-mediated protection/sensitivity against host AMPs might be important for the maintenance of latent infections.