Exploratory Chemistry on a new antibiotic

Period of Performance: 06/16/2016 - 05/31/2017

$746K

Phase 2 SBIR

Recipient Firm

Novobiotic Pharmaceuticals, LLC
Cambridge, MA 02138
Principal Investigator

Abstract

This project studies the structure-activity relationship (SAR) of the newly discovered antibioticteixobactin, with the goal of delivering a candidate that has development advantages over the parentcompound. Teixobactin is an unusual depsipeptide that is the first member of a novel class of peptidoglycansynthesis inhibitors. Teixobactin targets lipid II, peptidoglycan precursor, and lipid III, teichoic acid precursor. Itbinds to undecaprenyl-PP-sugars, which are not known to be modified, as opposed to a later lipid II-d-ala-d-alamodifiable form targeted by vancomycin. This unique mode of action, binding to two targets, neither of which isa protein, suggests that resistance will be very difficult to develop. To date, no resistance has been detected.Teixobactin has potent activity against a broad range of Gram-positive bacteria - S. aureus MRSA, S.pneumoniae, B. anthracis, M. tuberculosis, E. faecalis and E. faecium. It is active against resistant forms ofthese pathogens, including vancomycin-resistant enterococci. Teixobactin was highly efficacious in a murineMRSA septicemia and thigh infection models, and against S. pneumoniae in a lung infection model. Teixobactin itself is moving into development. However, studies of teixobactin have identified aproperty of the compound that can be improved. Teixobactin has a tendency to gelate in serum, which maypresent a problem depending on the dosing regimen required for humans (e.g., if higher serum concentrationsof the drug are required for humans than mice), and has presented a challenge in administering the compoundat higher doses in preclinical studies. Gelation of small peptides is a well-known phenomenon that has beensuccessfully addressed with medicinal chemistry optimization. We will conduct a medicinal chemistry campaignto gain a good understanding of the SAR of the molecule, and use this information to produce analogs that donot gelate but retain potent antibacterial properties. Early, proactive understanding of the SAR of teixobactinwould also guide the design of new analogs that could address additional issues that may come up during thedevelopment of teixobactin itself. An evaluation of the effect of modifying a variety of positions in the molecule will be conducted,through both semisynthetic and fully synthetic approaches. Several analogs have already been produced byboth approaches, which demonstrate the feasibility of the approach. Multiple analogs will be produced andtested for antibacterial activity, lipid II binding, gelation, and in vitro ADMET properties. Three analogs withreduced gelation but favorable in vitro properties will be selected for mouse studies including MTD, PK, andefficacy against MRSA in the thigh infection model. The results of this project will produce a therapeutic leadcandidate ready to enter further development including IND-enabling studies.