BMS-833923

The rapid emergence and spread of multi-drug- or pan-drug-resistant bacterial pathogens, such as ESKAPE, pose a serious threat to global health. However, the development of novel antibiotics is hindered by difficulties in identifying new antibiotic targets and the rapid development of drug resistance. Drug repurposing is an effective alternative strategy for combating antibiotic resistance that both saves resources and extends the life of existing antibiotics in combination treatment regimens. Screening of a chemical compound library identified BMS-833923 (BMS), a smoothened antagonist that kills Gram-positive bacteria directly, and potentiates colistin to destroy various Gram-negative bacteria. BMS did not induce detectable antibiotic resistance in vitro, and showed effective activity against drug-resistant bacteria in vivo. Mechanistic studies revealed that BMS caused membrane disruption by targeting the membrane phospholipids phosphatidylglycerol and cardiolipin, promoting membrane dysfunction, metabolic disturbance, leakage of cellular components, and, ultimately, cell death. This study describes a potential strategy to enhance the efficacy of colistin and combat multi-drug-resistant ESKAPE pathogens.

Ameloblastoma (AB) is an odontogenic tumor that arises from ameloblast-lineage cells. Although relatively uncommon and rarely metastatic, AB tumors are locally invasive and destructive to the jawbone and surrounding structures. Standard-of-care surgical resection often leads to disfigurement, and many tumors will locally recur, necessitating increasingly challenging surgeries. Recent genomic studies of AB have uncovered oncogenic driver mutations, including in the mitogen-activated protein kinase (MAPK) and Hedgehog signaling pathways. Medical therapies targeting those drivers would be a highly desirable alternative or addition to surgery; however, a paucity of existing AB cell lines has stymied clinical translation. To bridge this gap, here we report the establishment of 6 new AB cell lines—generated by “conditional reprogramming”—and their genomic characterization that reveals driver mutations in FGFR2, KRAS, NRAS, BRAF, PIK3CA, and SMO. Furthermore, in proof-of-principle studies, we use the new cell lines to investigate AB oncogene dependency and drug sensitivity. Among our findings, AB cells with KRAS or NRAS mutation (MAPK pathway) are exquisitely sensitive to MEK inhibition, which propels ameloblast differentiation. AB cells with activating SMO-L412F mutation (Hedgehog pathway) are insensitive to vismodegib; however, a distinct small-molecule SMO inhibitor, BMS-833923, significantly reduces both downstream Hedgehog signaling and tumor cell viability. The novel cell line resource enables preclinical studies and promises to speed the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms.