Dr Wolfgang Mutter, HyPharm GmbH; Dr Sonja Molinaro, HyPharm GmbH
Current strategies to eradicate antibiotic-resistant pathogens from the microbiomes of risk patients are scant. Available approaches rely on broad-spectrum antibiotics e.g. for eradication of Staphylococcus aureus from human noses with the antibiotic mupirocin. Because general inhibition of the microbiota bears severe risks of resistance development, outgrowth of other pathogens, or rapid recolonization by the same pathogen, highly selective, yet efficient and rapid eradication strategies are urgently needed. Bacteriolytical proteins derived from bacteriophages are discussed as alternative antiinfective strategies. They combine fast bactericidal properties, stability and activity at various environmental conditions, and high selectivity to bacterial target species. Specific lytic phage proteins could enable new, highly effective eradication strategies to overcome increasing mupirocin resistance (MupR) and simplify the complicated and lengthy mupirocin treatment regimen. We developed engineered lytic proteins derived from the S. aureus phage K and the bacteriocin lysostaphin, which were found to act very efficiently against S. aureus including diverse methicillin-resistant S. aureus (MRSA) lineages while clinical strains of coagulase-negative staphylococci were not affected. Our optimized product candidate HY-133 was engineered to specifically address unmet medical needs for a decolonization agent that is (i) highly efficient, acting fast in a bactericidal fashion, ideally within a few hours prior to or subsequent to hospital admission, (ii) resistance-breaking to MupR isolates and itself subject to low rates of resistance formation, and (iii) highly species-specific for S. aureus, both methicillin-susceptible S. aureus (MSSA) and MRSA, without influence on the co-colonizing nasal microbiome.
This project aims to tackle nasal colonization by S. aureus using an engineered bacteriophage-derived lysin. HY-133 is a recombinant chimeric lysin with two distinct functional domains: (i) containing a histidine-dependent aminopeptidase/hydrolase (CHAP) domain from the endolysin of phage K and (ii) a cell wall binding (CBD) domain from the bacteriocin lysostaphin. These two functional domains are connected via an engineered synthetic linker peptide to confer optimum enzymatic activity and resistance to protease attack. HY-133 cleaves the bacterial peptidoglycan between the d-alanine of the stem peptide and glycine of the cross-bridge peptide, with absolute target specificity for S. aureus. This cleavage leads to a destabilization of the cell envelope and consequently to the disruption of the cell. This principle has been tested successfully against a number of S. aureus isolates (1196 strains), while 192 coagulase-negative staphylococci (CoNS) were tested non-susceptible.
HY-133 is offered for licensing and co-development.
Pre-GMP and GMP production as well as gel formulation development are ongoing and non clinical assessment will start this year.
First priority was filed in December 2009 (WO2011076432). In the meantime Hypharm filed a variety of patents covering this technology: EP2188373 (B1), WO2009024327
Idelevich EA et al. (2011). Antimicrob Agents Chemother. 55(9):4416-9
Idelevich EA et al. (2016): Antimicrob Agents Chemother. 25;60(4):2551-3