Lamya El Mortaji
Aurobac Therapeutics
Lamya El Mortaji, PhD, is a microbiologist and biotechnology researcher with over 15 years of experience in antimicrobial discovery, bacterial pathogenesis, and molecular microbiology. She led R&D projects at DEINOVE, focusing on high-throughput and microfluidic screening of novel antibiotics and antifungals. Her academic research at Institut Pasteur and Harvard Medical School centred on bacterial RNA metabolism and genetic tool development. She currently manages multidisciplinary laboratories at Aurobac Therapeutics, contributing to innovation in the fight against infectious diseases.
Affiliations: (1). AUROBAC Therapeutics
Rapidly lytic phage endolysin is an attractive novel modality for treating serious bacterial infections. To enhance penetration into Gram-negative (GN) bacteria, these peptidoglycan (PG) cell wall hydrolase enzymes are classically fused to an antimicrobial/cell penetrating peptide (AMP/CPP). A prototype of these engineered endolysins is ATX401 (formerly CF-370), described for its broad in vitro activity and potentiation of meropenem in animal models [Sauve et al. JID 2024]. We investigated the in vitro activity and in vivo efficacy of ATX401 and deciphered the key components driving the antibacterial activity but also limiting its potency in the presence of serum. ATX401 showed promising in vitro activity against carbapenem-resistant GN isolates in modified culture medium (DCAAT). However, activity was abolished by serum and efficacy in a rat lung infection model was very limited. Investigations of serum inhibition identified albumin binding rather than enzymatic degradation as the primary cause. Surprisingly, PG hydrolysis activity was maintained in the presence of serum, plus disruption of the lysin active site, while abolishing enzymatic activity, still facilitated antibacterial activity. The N-terminal CPP was subsequently shown to be as potent as ATX401, indicating limited contribution of the lysin domain to its antibacterial activity. These findings highlight challenges that must be overcome when developing GN lysins. (1) It is crucial to confirm the antibacterial MOA and that activity of the fusion product is greater than each component alone. (2) The product should retain antibacterial activity in the presence of serum. (3) Ideally, it should show activity in standard AST protocols.