Professor Martti Vaara, M.D., Ph.D.
CEO, CSO, Northern Antibiotics Oy
It does make complete sense. Most of the antibiotics of the “golden age of antibiotic discovery” have now been replaced by their improved versions.
This has happened to the archetypical betalactam, penicillin G. Now we use its fourth generation. The same is true of the first cephalosporin, cephalothin. Now we use its fifth generation.
Similarly, a majority of the well-known antibiotics, such as tetracyclines, aminoglycosides, macrolide antibiotics and quinolones, are today represented by their latest generation of more efficacious and tolerable versions.
True, brand new antibacterial compounds, isolated from nature or designed in silico, with an entirely new target or mode of action, are preferred by the investors and funding agencies. Rightly so.
Working with the old antibiotics, the good and bad characteristics of the compounds are already known. You can plan your modifications accordingly and predict the outcome with a certain degree of accuracy.
Today, we still use the first generation of polymyxins
Polymyxins were discovered in 1947. Their clinical use, however, was practically abandoned in the 1960s due to nephrotoxicity (rapid deterioration of kidney function) and because better-tolerated drugs belonging to other antibiotic classes were discovered.
Now, however, polymyxins have resurged as the last-resort drugs against extremely multi-resistant strains, despite the fact that their nephrotoxicity forces clinicians to administer doses that are lower than those required for optimal efficacy.
Complicated urinary tract infection (cUTI) which often leads to life-threatening blood-stream infection is the biggest single indication of the use of hospital antibiotics.
Time for the next generation of polymyxins?
Polymyxins bind strongly to the brush-border membrane (BBM) of the proximal tubular kidney cells and this results in their nephrotoxicity. Northern Antibiotics have designed, at preclinical stage, polymyxin derivatives1 that bind to the BBM at the rate of one tenth of that of the old polymyxin and that are some three times less nephrotoxic. On top of that the polymyxin derivatives are some 10 times more efficient in treating experimental E. coli urinary tract infection. Improved efficacy means lowered doses required and, you guess, the lowered doses mean that the adverse effects may be even further reduced.
The improved polymyxins may be most useful in treating complicated urinary tract infection (cUTI) which often leads to life-threatening blood-stream infection and is the biggest single indication of the use of hospital antibiotics.
1 Vaara M. 2019. Polymyxins and their potential next generation as therapeutic antibiotics. Frontiers in Microbiol 10, article 1689. doi: 10.3389/fmicb.2019.011689.
