A FtsZ inhibitor-acinetobactin conjugate with enhanced cellular uptake in Acinetobacter baumannii acts synergistically in combination with PBP3-targeting antibiotics

Abstract

Multidrug resistance in the Gram-negative bacterial pathogen Acinetobacter baumannii is a global public health threat, highlighting a critical need for drug development. FtsZ is an essential cell division protein that is an appealing target for new antibacterial agents. Benzamide-based FtsZ inhibitors have been developed that exhibit potent activity against Gram-positive pathogens, but poor activity against A. baumannii and other clinically significant Gram-negative pathogens. In this connection, we have initiated a program to enhance activity of benzamide FtsZ inhibitors via conjugation to iron-coordinating siderophore moieties that promote cellular uptake through endogenous bacterial siderophore-iron uptake pathways. Here, we describe a second-generation FtsZ inhibitor-siderophore conjugate (RUP7), in which an oxazole-benzamide FtsZ inhibitor is conjugated to acinetobactin, a principal native siderophore of A. baumannii. In iron-limiting conditions that are typically present at common sites of A. baumannii infection, RUP7 exhibits significantly enhanced activity against a library of A. baumannii clinical isolates relative to the non-conjugated FtsZ inhibitor (RUP2) or a first-generation conjugate (RUP4) in which RUP2 has been conjugated to a chlorocatechol siderophore functionality. This enhanced activity is correlated with markedly improved cellular uptake, perhaps via the BauABCDEF acinetobactin-iron uptake system, the expression of which is highly upregulated in iron-limiting conditions. RUP7 exhibits significant bactericidal synergy against A. baumannii when combined with clinical antibiotics that target penicillin binding protein 3 (PBP3 or FtsI), including aztreonam, piperacillin:tazobactam, cefsulodin, and ceftazidime. In the aggregate, our results highlight the combination of design-optimized FtsZ inhibitor-siderophore conjugates and PBP3-targeting antibiotics as an appealing therapeutic strategy for the treatment of A. baumannii infections.