Pleiotropic anti-infective effects of a small-molecule lipid II binder

Authors: DE LEEUW, ERIC - University Of Maryland School Of Medicine; KEE, SUNG HYEN - US Department Of Agriculture (USDA); KWASNY, STEVEN - Microbiotix Inc; OPPERMAN, TYMOTHY - Microbiotix Inc; Lillehoj, Hyun

Submitted to: Infection and Drug Resistance
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2018
Publication Date: 12/30/2018
Citation: De Leeuw, E.P., Kee, S., Kwasny, S.M., Opperman, T.J., Lillehoj, H.S. 2018. Pleiotropic anti-infective effects of a small-molecule lipid II binder. Infection and Drug Resistance. 62:381-387.

Interpretive Summary: Necrotic enteritis or NE is an enteric disease that affects commercial poultry. The causative agent is Clostridium perfringens or CP, a frequent cause of food poisoning in humans through the consumption of poultry products from infected chickens. Host immune response to CP involves both cellular components such as intestinal intra-epithelial lymphocytes as well as host defense peptides as first responders. Examples of such antimicrobial peptides include NK-lysin, produced by Natural Killer cells and cytotoxic T lymphocytes, and defensins, which are produced by mucosal surfaces. In this report, ARS scientists collaborated with University of Maryland scientist to identify low molecular weight synthetic compounds that bind Lipid II on the bacterial cell membrane. Following binding to Lipid II, these compounds act as antibacterials against Gram-positive organisms. After screening many compounds, Lipid II binder 1611-0203 show therapeutic potential to act as anti-infectives against various organisms simultaneously. This finding will enable industry to develop new antimicrobial therapeutics against CP.

Technical Abstract: We identified low molecular weight compounds that bind to Lipid II, an essential precursor of bacterial cell wall biosynthesis. Following binding to Lipid II, these compounds act as antibacterials on multiple biosynthesis pathways with specificity against Gram-positive organisms. Here, we have tested a small subset of our most promising leads against the bacterium Clostridium perfringens and sporozoites of Eimeria tenella, an intracellular protozoan parasite that cause intestinal disease in poultry. We find one compound, 1611-0203 (2-{2,3,5,6-tetrafluoro-4-[2,3,5,6-tetrafluoro-4-(2 hydroxyphenoxy) phenyl]phenol) to specifically inhibit growth of both agents. In addition, compound 1611-0203 inhibits Staphylococcus aureus and Enterococci spp. specifically. Mechanism-of-action studies further reveal that 1611-0203 primarily affects cell wall biosynthesis followed by inhibition of multiple biosynthetic pathways. Combined, our results indicate that Lipid II binders such as 1611-0203 have therapeutic potential to act as anti-infectives against various organisms simultaneously.