Arietis is developing first-in-class small molecule antibiotics to kill drug resistant bacterial pathogens and treat infections with a high unmet clinical need.
Courtesy of Dr. Richard Lee
TECHNOLOGY
Imagine if antibiotics worked against complicated infections such as prosthetic joint infections, endocarditis, and osteomyelitis, and common infections were cured more quickly and effectively.
This should be possible for the first time since Arietis is developing novel proprietary antibiotics that activate the ClpP protease and cause cells to self-digest. This unique “activating” mechanism causes rapid and exceptional killing of the highly resistant “ESKAPE” pathogens Staphylococcus aureus and Enterococcus faecium, as well as the leading cause of acute bacterial respiratory infections, Streptococcus pneumoniae.
Killing by ClpP activation is effective against even non-growing cells, in contrast to other antibiotics, which target processes that are inactive in non-growing cells. Many bacteria can evade killing by traditional antibiotics, even surviving high concentrations for prolonged periods, by simply growing slowly or not at all. These survivors contribute to antibiotic resistance, cause recurrent infections, and explain why traditional antibiotics are unable to kill biofilms, which have restricted access to the immune system.
However, bacteria cannot escape death by shutting down or waiting until antibiotic levels drop when ClpP is activated. Combining ClpP activators with traditional antibiotics prevented resistance development and caused eradication of MRSA infections in animal models where traditional antibiotics failed due to biofilms. This strategy may allow complicated infections to be cured with antibiotics for the first time and common infections to be treated more quickly and effectively with less recurrence.
It is important not to overlook the ongoing threat of antimicrobial resistance in Gram positive pathogens:
- There are more deaths in the US from infections caused by drug resistant gram positive pathogens (MRSA, VRE and drug resistant S. pneumoniae) compared to the gram negatives (carbapenem-resistant Enterobacteriaceae, multidrug-resistant Pseudomonas and Acinetobacter).
- There is still a high unmet need for novel antibiotics to treat drug resistant Gram positive infections especially for complicated infections such as endocarditis, osteomyelitis, diabetic ulcers, prosthetic joint and catheter related infections.
PUBLICATIONS
Griffith EC, Zhao Y, Singh AP, Conlon BP, Tangallapally R, Shadrick WR, Liu J, Wallace MJ, Yang L, Elmore JM, Li Y, Zheng Z, Miller DJ, Cheramie MN, Lee RB, LaFleur MD, Lewis K, Lee RE. Ureadepsipeptides as ClpP Activators. ACS Infect Dis. 2019 Nov 8;5(11):1915-1925.
Mroue N, Arya A, Brown Gandt A, Russell C, Han A, Gavrish E, LaFleur M. Pharmacodynamics of ClpP-Activating Antibiotic Combinations against Gram-Positive Pathogens. Antimicrob Agents Chemother. 2019 Dec 20;64(1).
Brown Gandt A, Griffith EC, Lister IM, Billings LL, Han A, Tangallapally R, Zhao Y, Singh AP, Lee RE, LaFleur MD. In Vivo and In Vitro Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci. Antimicrob Agents Chemother. 2018 Aug;62(8).
Conlon, B. P., E. S. Nakayasu, L. E. Fleck, M. D. LaFleur, V. M. Isabella, K. Coleman, S. N. Leonard, R. D. Smith, J. N. Adkins & K. Lewis, (2013) Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503: 365-370.
Gavrish, E., B. Shrestha, C. Chen, I. Lister, E. J. North, L. Yang, R. E. Lee, A. Han, B. Williams, D. Charnuska, K. Coleman, K. Lewis & M. D. LaFleur, (2014) In Vitro and In Vivo Activities of HPi1, a Selective Antimicrobial against Helicobacter pylori. Antimicrobial Agents and Chemotherapy 58: 3255-3260.
Michael LaFleur, Sun L., Keating J., Lister, I., Nantel A., Long L., Ghannoum M., North J., Lee R., Coleman K., Dahl T., Lewis K. (2013) Potentiation of Azole Antifungals by 2-adamantanamine. Antimicrob. Agents Chemother. 57(8):3585-92.
Lewis K. (2013) Platforms for antibiotic discovery. Nat Rev Drug Discov 12:371-387.
about arietis
Arietis is located at the Bio Square Discovery and Innovation Center on Boston University's Medical Campus. Arietis was founded on technologies for discovering antimicrobials developed by Professor Kim Lewis at Northeastern University. Dr. Michael LaFleur oversees daily laboratory operations. Following is a brief description of their backgrounds.
Kim Lewis, Ph.D.
Founder & Chairman of the Board
Dr. Lewis is a Professor of Biology and Director of the Antimicrobial Discovery Center at Northeastern University. He is an expert in microbial drug resistance and drug discovery. He received his Ph.D. in Biochemistry from Moscow University and prior to coming to NEU in 2001 has been on the Faculty of MIT, University of Maryland and Tufts University. Dr. Lewis is the author of over 100 publications, several patents and inventions licensed to the Industry.
Michael LaFleur, Ph.D., MBA
Chief Executive Officer
Dr. LaFleur is a co-inventor on key Arietis technology and has led operations for the past decade. Michael received his Ph.D. from Northeastern University and an MBA from the Isenberg School of Management. He has worked closely with Dr. Lewis to understand recalcitrant infections, and develop therapeutic approaches to make these infections treatable.
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