Background
Antimicrobial resistance (AMR) is an escalating threat to human health, with the potential to cost the global economy trillions of dollars. As resistant pathogens develop, treating common infections becomes increasingly difficult, routine medical procedures become riskier, and the demand for new antimicrobial treatments grows more urgent each year. AMR is a problem for all countries at all income levels and combating AMR requires a global action plan. According to WHO, the global rise in AMR is alarming and commitment to radically scale-up efforts to combat antimicrobial resistance is necessary. The key facts about and actions to address AMR can be found at https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance. A recent update to the Bacterial Priority Pathogens List offers guidance on developing new and essential treatments to combat the spread of antimicrobial resistance. The LeadtoTreat project addresses the AMR threat by enabling targeted delivery of novel lead compounds with low drugability as well as synergistic combinations of antibiotics and potentiators in a nano-formulation.
SINTEF and NTNU in Trondheim, Norway, have for many years had joint activities within marine bioprospecting, i.e. mining environmental microbial isolates for new bioactive compounds with potential to enter the antimicrobial market. Our proof of principle compound in LeadtoTreat resulting from these activities is MBL-AB01, produced by an Actinobacterium belonging to the Actinalloteichus taxon (98.97% 16S rRNA gene similarity to Actinalloteichus hymenacidonis HPA177)6. The MBL-AB01 (C27H18ClNO10, Patent application ref NO20160680) belongs to the xanthone class of compounds and shows a very high antibiotic activity in vitro against Gram-positive bacteria, including multi drug resistant strains of MRSA and vancomycin-resistant Enterococcus strains. (e.g. 50-100 times better MIC than vancomycin for MRSA).
MBL-AB01 has significant structural relationship to other xanthones such as xantolipins, but according to our data with a lower toxicity towards mammalian cells. Due to the high antimicrobial activity, MBL-AB01 may represent an interesting lead compound for further development into a potent antimicrobial agent. However, low activity was observed when the compound was tested in an in vivo MRSA mouse model. These results are most likely due to absorption to protein in the blood stream, as addition of protein (bovine serum albumin) in vitro significantly reduces the antibacterial activity of MBL-AB01. In addition, the compound has very poor water solubility and is therefore difficult to deliver intravenously. MBL-AB01 thus represents an example of an antibiotic candidate that has excellent biological activity but has other inherent properties that makes the molecule difficult to utilize in clinic.
The LeadtoTreat project develops drug formulations that are specifically targeting pathogenic bacteria using nanobodies. Nanobodies, also known as single-domain antibodies, are a specialized type of antibody fragment derived from the unique immune systems of camelids like llamas and alpacas. Unlike traditional antibodies, which consist of two heavy and two light chains, camelids naturally produce a distinctive subclass of antibodies that lack light chains, known as heavy-chain-only antibodies. From this subclass, nanobodies are derived. Nanobodies are ten times smaller and simpler in structure compared to conventional antibodies. Their smaller size makes them highly stable and easier to produce and modify.
The small size of nanobodies offers several advantages. They can reach targets that larger antibodies struggle to access, such as enzyme active sites or difficult to excess parts of proteins. This ability makes them especially useful in medical applications like targeted drug delivery or diagnostic imaging, where precise targeting is crucial. In the context of nano-formulation delivery systems designed to transport drugs specifically to intended sites in the body, nanobodies can be conjugated to nanoparticles. This conjugation allows the nano-formulation to selectively bind to certain cells or tissues that express the corresponding antigens. The process of obtaining nanobodies is less invasive compared to traditional methods of antibody production. Alpacas are given a small, harmless dose of an antigen, and after a few weeks, a small blood sample is taken. Researchers can then isolate and sequence the nanobodies from this sample and produce them recombinantly in bacteria or by cell culture means. This method is gentler than techniques used in other animals, such as mice or rabbits, and poses fewer ethical concerns. The nanobody expertise is brought to the consortium by NanoTag Biotechnologies.