Aminospectinomycin antibacterials for the treatment of antibiotic-resistant gonorrhea and other bacterial STDs

Summary AbstractThe overall objective of this project is to test and prioritize aminospectinomycinamSPCantibacterials for use as broad spectrum agents against bacterial sexually transmitted diseasesSTDsThe amSPCslike their parent antibioticspectinomycinSPCact by inhibiting bacterial protein synthesis by binding to a ribosomal site that is unique among aminoglycosides and other protein synthesis inhibitorsGonorrheacaused by the bacterium Neisseria gonorrhoeaeis a STD that afflicts only humansThe disease can be asymptomatic and undiagnosed infections can lead to pelvic inflammatory disease andultimatelyinfertility or may disseminatecausing joint and skin manifestationsTherapeutic options consist of ceftriaxonemg intramuscular in a single doseplus azithromycingram orally in a single doseor doxycycline dosed orally fordaysNgonorrhoeae has acquired resistance to all agents that have been used as therapyfrom thes when sulfonamides were used as monotherapy until current times where resistance is developing to ceftriaxone and other extended spectrum cephalosporinsInfections caused by Chlamydia trachomatis are even more prevalent than gonorrheal infections andalthough antibiotic resistance is a smaller problempeople with chlamydial infections are often co infected with other sexually transmitted bacterial pathogens such as Treponema palladumsyphilisHaemophilus ducreyi and Mycoplasma genitaliumNew small molecule drugsespecially those with synergy with new or existing antibioticsrendering them useful for combination therapyare desperately needed and the drug pipeline is very limitedWe have discovered a series of novel amSPCswhich are derivatives of SPCa second line gonorrhea agent still in use outside of the United StatesThe structure activity data available to date demonstrates an excellentfoldimprovement in in vitro potency compared to SPC and low cytotoxicity against multiple cell linesThe amSPCs represent a safe potential new treatment option for drug resistant gonorrhea and bacterial co infectionsThe low oral bioavailability of the amSPCs suggests that they would be administered parenterallyas is standard for aminoglycoside antigonorrheal drugs and the current standard of carecefriaxoneThe goal of this Phase I research project is to develop the amSPCs as a parenteral therapy for the treatment of bacterial STDs bymaintaining potency against Ngonorrhoeae and Ctrachomatisshowing efficacy against other bacterial STDs anddemonstrating efficacy in a mouse model of gonorrheaOur strategy is to evaluate and prioritize existing analogsrtto demonstrate a broad spectrum potency against bacterial STD speciesmaintain low toxicity against mammalian cell lines and maintain or improve in vivo efficacyIn Phase IIwe will evaluate the in vivo efficacy of the lead compounds emerging from Phase I in additional murine models of Ng infection and Ng Ct co infection and conduct pharmacokinetic and toxicology studies to establish an in vivo safety index and select the final broad spectrum STD candidate suitable for IND enabling preclinical GLP studies