New Achaogen LpxC Publication
Frederick Cohen
Head of Medicinal, Analytical, & Computational Chemistry at Nurix Therapeutics
I’m proud to highlight the publication of Achaogen’s effort to develop a novel LpxC inhibitor for the treatment of P. aeruginosa infections.
This manuscript covers the 5 years of tremendous effort by a talented team after the clinical development of ACHN-975 was discontinued. We developed a high-content assay that recapitulated the cardiovascular (CV) effects seen in the Phase 1 trial. Over 20 compounds were scaled-up to gram quantity to enable screening through this assay. We concluded that compounds with a basic amine (pKa >6.5) displayed a low therapeutic window, whereas non-basic compounds were significantly safer. I believe these results have implications for Medicinal Chemistry in general, well beyond this specific work. We selected a molecule that offered the best combination of anti-bacterial activity, pharmacokinetics, and CV safety. Development of a phosphate prodrug enhanced solubility to enable preclinical evaluation. Unfortunately, upon dose-escalation of the prodrug, the CV effects were observed again. At this point, we were unable to continue this project, so no further investigation was done. Was our hypothesis about basic amines wrong? or does the prodrug produce a similar effect through a different mechanism? All of this is discussed in more detail in the paper.
This paper contains a message about the development of new antibiotics for Gram-negative pathogens. Currently research in the field is highly focused on solving the permeability problem. However, even when that problem is ‘solved’ there are two more hurdles that must be crossed. The LpxC inhibitors discussed in our work were highly permeable across both membranes of Gram-negative bacteria. Yet, we still need very high doses to reach therapeutic levels, as bacteria are very hard to kill, relative to say cancer cells. We estimated that we would need > 1 g/day to treat our target population. These doses bring a high risk for off-target activity. Thus, new molecules must be extremely clean of acute toxicities, a hurdle we were unable to jump.
The second big problem is one we actually did not face on this project: the mutation liability for single-target antibiotics. Single targets are cases where one protein is encoded by one gene and inhibited by one molecule. There are NO examples of Gram-negative antibiotics that have this 1:1:1 ratio. More on this subject in two upcoming publications. The first delves deeply into the microbiology of these LpxC inhibitors, including mechanisms of resistance. The second discloses our work to optimize inhibitors of bacterial biotin carboxylase (AccC), a project that was scuttled by resistance. Please stay tuned…
tl;dr: To develop new antibiotics against cytoplasmic targets, molecules must be permeable through orthogonal membranes, very safe, and immune to single base pair flips.
Lynk Pharmaceuticals - Co-Founder and Chief Science officer
5 年I am very happy to see the new publication on LpxC inhibitors. If we can overcome the LpxC, many anti-Gram-positive agents can be used for Gram-negative. ??
Great that you are publishing this. A strong illustration of how hard the problem of discovering and developing new anti-Gram negative agents is. And this case is representative of the problems others have seen with single Gram negative targets, permeability, toxicity and also mutational resistance. While there is much rumbling about the financial difficulties of antibacterial development (which is true), it should be recognized that many scientists at companies small and large have tried to come up with novel agents with novel targets that pass preclinical muster for >50 years with little progress. So even if the push/pull incentives come into play, I fear it is unlikely that such new stuff will come easily. We may be stuck with improvements on the old targets and classes for a long time. Yes, alternatives may be found, with combinations, adjuncts, antivirulence, host affectors, but I don’t think that solving the money problem will lead to a spate of new drugs. We will see. Anyway, nice work ex-Achaogenites.
Drug hunter - Team builder - Biotech executive
5 年Interesting work, thank you for publishing. Maybe a place where a combo approach with a potentiator to enable lower doses of compound to achieve efficacy??
Antibacterial drug discovery - Scientific consultant and microbiologist
5 年Good science with a disappointing final outcome.? Very glad you published this work.
Endowed Chair of Medicinal Chemistry, Chemical Biology and Therapeutics, St. Jude Children's Research Hospital
5 年Many good points, well done