It is becoming increasingly recognized that bacterial antibiotic resistance is outstripping the development of new antibiotic therapeutics, and some authorities even warn of a return to the pre-antibiotic era, where life-threatening infections cannot be successfully treated.
Macrolides are among the most widely used, most effective and safest antibiotics to reach clinical practice; in fact, azithromycin has been among the world’s most widely used antibiotics for the past several years. But, while current macrolides are highly effective against some major bacteria, they are ineffective against others, especially gram-negative bacteria, the cause of most serious infections in the US.
The first three generations of macrolides have very limited activity against gram-negatives, and the sole drug in the current fourth generation, solithromycin, has only slightly greater activity. Within other antibiotic classes, a limited number of compounds are in development to treat resistant gram-negative infections, and even fewer are available both intravenously and orally, as would be expected with macrolides.
The transformative new technology developed by Prof. Andrew Myers for the first time enables a practical, intrinsically scalable and readily diversifiable, total synthesis of macrolide structures from basic building blocks. The synthesis has been proven in the laboratory, and is already producing significant numbers of novel, fifth generation macrolide compounds for testing. In fact, more than 200 completely novel macrolides have already been synthesized with excellent yields, indicating that the synthetic route is commercially viable. In vitro testing of these new compounds indicates that several compounds from multiple different “scaffolds” have activity approaching clinical effectiveness against highly resistant gram-negative bacteria. In addition, a number of compounds are highly active against gram-positive bacteria including resistant clinical strains, potentially even more active than currently available macrolides.