NSC60339

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for the development of effective EPIs, especially in light of constantly emerging resistance. Here, we describe EPIs that interact with periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes, and potentiate the activities of antibiotics in Escherichia coli and other Gram-negative bacteria. Our findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.

Forty-two exptl. tumors and leukemias from mice and rats were stored at -195° for periods up to 6 years.They remained transplantable and lethal to their inoculated hosts.A bioassay, which estimated the surviving cell population based on the cell kinetics of exponentially growing neoplasms in vivo, demonstrated an initial loss of viable cells due to the freezing procedures and no further losses due to storage.The response of 14 drug-induced neoplasms resistant to chemotherapeutic agents methotrexate (NSC 740), 2-chloro-4',4"-di-2-imidazolin-2-yl terephthalanilide-2HCl (NSC 38280); and its free base (NSC 60339), cytosine arabinoside (NSC 63878), 6-mercaptopurine (NSC 755), 4',4"-bis(2-imidazolin-2-ylamino) terephthalanilide-2HCl, (NSC 53306), N,N"-bis(p-N'-methylamidinophenyl) terephthalamidine-4HCl (NSC 57155), vincristine (NSC 67574), vinblastine (NSC 49842), methyl-GAG(NSC 32946), azaserine (NSC 742), cytoxan (NSC 26271), and 2-amino-4,6-dimercaptopurine (NSC 29189) remained unchanged after long term storage.