| Summary: | The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. Here, we describe a third-generation MreB inhibitor (TXH11106) with enhanced bactericidal activity versus the Gram-negative pathogens <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, and <i>Pseudomonas aeruginosa</i> compared to the first- and second-generation compounds A22 and CBR-4830, respectively. Large inocula of these four pathogens are associated with a low frequency of resistance (FOR) to TXH11106. The enhanced bactericidal activity of TXH11106 relative to A22 and CBR-4830 correlates with a correspondingly enhanced capacity to inhibit <i>E. coli</i> MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in <i>E. coli</i>, <i>K. pneumoniae</i>, <i>A. baumannii</i>, and <i>P. aeruginosa</i> provide further evidence supporting MreB as the bactericidal target of the compound. Taken together, our results highlight the potential of TXH11106 as an MreB inhibitor with activity against a broad spectrum of Gram-negative bacterial pathogens of acute clinical importance.
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