Two-partner secretion system transporter proteins (TpsB) are widely conserved across Gram-negative pathogens. TpsB family proteins secrete exoprotein virulence factors that perform a myriad of functions such as adhesion and immune modulation. Despite their incredible importance in bacterial infectious disease, TpsB inhibitors have not yet been discovered. Here, we describe a potent inhibitor of FhaC, a TpsB protein produced by Bordetella spp . FhaC secretes the exoprotein FhaB that is essential for the establishment of whooping cough. We designed a peptide called P1 that we predicted would prevent substrate binding and lock FhaC in a secretion-inactive state. Simulations and biochemical assays supported our hypothesis and identified interactions important for P1 binding to FhaC. Strikingly, we observed that the peptide strongly inhibited FhaB secretion from clinical isolates and broadly reduced correlates of virulence. Together, this work provides a strong case for further development of a novel class of anti-TpsB anti-virulence compounds. ### Competing Interest Statement The authors have declared no competing interest. National Institute of Allergy and Infectious Diseases, R21AI180112

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