The increasing prevalence of antibiotic resistance among bacterial pathogens is projected to cause up to 10 million deaths/yr by 2050 if new antibiotics, preferably with new mechanisms of action, are not developed. Drug-resistant Neisseria gonorrhoeae is among the five most dangerous "Urgent Threats" identified by the CDC. In this regard, a novel series of acylaminooxadiazoles that selectively inhibits trans-translation, resulting in broad-spectrum antibiotic activity was discovered. The synthesis of acylaminooxadiazoles was achieved following literature procedures from readily available starting materials and their biol. activities were evaluated in in vitro and in vivo assays. Compounds in the series demonstrated potent broad-spectrum antibiotic activity against Gram-pos. species and many Gram-neg. species, including N. gonorrhoeae. The lead acylaminooxadiazole, MBX-4132, exhibited 95% oral bioavailability, excellent plasma exposure (AUC 181,000 h*ng/mL), half-life (3.6 h) and a low clearance rate (72.6 mL/h/kg), and is excreted renally unchanged. Moreover, MBX-4132 was well-tolerated in mice at a single dose of 100 mg/kg, or repeat dosing at 10 mg/kg (BID, 7 d) and was efficacious in a murine model of genital tract infection at a single oral dose of 10 mg/kg, reducing bacterial load to undetectable levels in 80% of mice within 7 days.