You have accessJournal of UrologyPediatrics: Urinary Tract Infection & Vesicoureteral Relux1 Apr 2014MP44-10 DEVELOPMENT OF GENTAMICIN ANALOGS WITH LESS ORGAN TOXICITY AND PRESERVED ANTI-UROPATHOGEN ACTIVITY Yi-Ju Hsieh, Anthony Ricci, Alan Cheng, and Michael Hsieh Yi-Ju HsiehYi-Ju Hsieh More articles by this author , Anthony RicciAnthony Ricci More articles by this author , Alan ChengAlan Cheng More articles by this author , and Michael HsiehMichael Hsieh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1385AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Although aminoglycosides are a mainstay among antibiotics, this class of antimicrobials features risks of inducing hearing loss and nephrotoxicity. These concerns have limited the use of aminoglycosides despite their proven efficacy. Thus, we sought to develop analogs of gentamicin with reduced potential for oto- and nephrotoxicity and preserved antimicrobial activity. Methods We used an iterative approach of drug design and synthesis followed by testing of ototoxicity, nephrotoxicity, and antimicrobial activity. Rat cochleas were exposed to drugs in vitro, and hair cell survival was confirmed by immunostaining. Bacterial minimal inhibitory and bacteriocidal concentrations (MIC and MBC) were calculated for drugs using standard methods. Hearing testing was performed on mice administered drugs and furosemide. Mice given drugs alone underwent testing of serum creatinine. Urine, bladder, and kidney colony forming units of bacteria were measured in mice transurethrally infected with uropathogenic E. coli (UTI89 strain) and given drugs. Results Of various gentamicin analogs identified, SPK101 N2 was selected for more extensive testing due to favorable characteristics. SPK101 N2 featured similar MIC and MBC to sisomicin, a gentamicin analog. SPK101 N2 also exhibited less ototoxicity both in vitro and in vivo and no nephrotoxicity in vivo as assessed by serum creatinine. At all drug doses tested (25 μg, 125 μg, and 625 μg/dose given five times every 2 hours) SPK101 N2 reduced bacterial burdens in urine, bladders, and kidneys relative to no antibiotics, and similar to the parent compound sisomicin. Conclusions SPK101 N2 is a very promising gentamicin analog that features decreased oto- and nephrotoxicity with preserved antimicrobial activity, including in models of urinary tract infection. Ongoing work will test the efficacy of this gentamicin analog in other infection models. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e446 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yi-Ju Hsieh More articles by this author Anthony Ricci More articles by this author Alan Cheng More articles by this author Michael Hsieh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...