In this work we use stable isotope labeling of amino acids in cell culture (SILAC) and a S. Typhimurium mutant that secretes increased amounts of effectors to identify cognate effector binding partners during infection. Using this method, we identified the host protein annexin A2 as a binding partner for both SopD2 and PipB2 and were able to confirm its binding to SopD2 by reciprocal pull down. This indicates that SopD2 and PipB2 likely both interact with annexin A2 through protein-protein interactions to establish the S. Typhimurium intracellular replicativeniche. This demonstrates the value of studying effector interactions using proteomic techniques and natural effector delivery during infection rather than transfection.