Polymyxins: From Phasing Out to Comeback — Evolution of a “Powerful Weapon” Against Drug-Resistant Bacteria

Polymyxins

are a class of cyclic polypeptide antibiotics produced by Paenibacillus polymyxa. Although the producing strain belongs to Gram-positive bacteria, polymyxins exhibit significant antibacterial activity against Gram-negative bacteria. As natural antibiotics, polymyxins are widely distributed in soil and plant microecosystems.

Classification and Structure of Polymyxins

Polymyxins mainly include five types: A, B, C, D, and E. Among them, polymyxin B and polymyxin E are the most commonly used in clinical practice. The structures of polymyxin B and polymyxin E are very similar, differing at only one amino acid position: the R2 position of polymyxin B is D-Phe, whereas the R2 position of polymyxin E is D-Leu.

▲ Structure of polymyxins

Image source: Synthesis of Best-Seller Drugs, 2016

Formulations for Clinical Use

Polymyxin B: the commonly used drug is polymyxin B sulfate (PMB).

Polymyxin E: commonly used drugs include colistin sulfate and colistin methanesulfonate (CMS).

Development History of Polymyxins

Polymyxins were first isolated from Paenibacillus polymyxa in 1947 and introduced into clinical use in 1959. In the 1950s, polymyxins became one of the main drugs for treating Gram-negative bacterial infections. However,

due to their significant nephrotoxicity, they were gradually replaced by safer antibacterial drugs such as β-lactams starting in the 1970s.

Since the beginning of the 21st century, with the widespread emergence of carbapenem-resistant bacterial infections worldwide, the drug-resistance situation of bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae has become increasingly severe.

Due to limited available drug options, polymyxins have been reintroduced clinically as part of combination therapies to combat these multidrug-resistant Gram-negative bacteria. Polymyxins have become a last-line drug for treating infections resistant to other antibiotics, especially carbapenem-resistant Enterobacteriaceae (CRE) infections.

Current Clinical Application

   The growing clinical demand is directly reflected in market data. According to statistics, in 2021, sales of polymyxin drugs in Chinese hospitals reached approximately RMB 1.914 billion, a year-on-year increase of 61.49%. Sales in the first half of 2022 already reached RMB 1.254 billion. These figures reflect the importance of polymyxins in clinical application, as well as the urgency of treating drug-resistant bacterial infections and their market potential.

In China, polymyxin B sulfate for injection is an exclusive product of Shanghai Shangyi Biochemical Pharmaceutical Co., Ltd., and is the only approved formulation on the market, classified as a Category B drug under medical insurance. In recent years, as the problem of antibacterial drug resistance has become increasingly serious, the market size of this product has grown rapidly. Hospital sales increased from RMB 157 million in 2018 to nearly RMB 1.7 billion in 2022, with a compound annual growth rate of 82.3%.

Development of Next-Generation Polymyxins

To address the toxicity of traditional polymyxins, next-generation polymyxin drugs are under development. For example, MRX-8 is a novel polymyxin antibacterial drug used to treat multidrug-resistant Gram-negative bacterial infections.

The main features of MRX-8 include:

• Broad-spectrum antibacterial activity: effective against a variety of clinically relevant drug-resistant Gram-negative strains, including carbapenem-resistant strains.
• Significantly reduced nephrotoxicity: in vitro experiments show that its toxicity to kidney cells is far lower than that of traditional polymyxins.
• Excellent in vivo efficacy: in animal lung infection models, it shows better antibacterial effects than traditional polymyxins.
• Improved manufacturing process: chemical synthesis is used to improve product purity and quality stability.

MRX-8 is currently undergoing Phase I clinical trials in China and the United States. The results of the US Phase I clinical trial published in October 2022 showed that at the anticipated therapeutic dose, MRX-8 had acceptable safety and pharmacokinetic characteristics consistent with expectations in healthy subjects.

Screenshot source:

https://www.micurx.com/1210.html

Market Prospects and R&D Trends of Polymyxins

Market data clearly demonstrate the clinical demand and growth trend of polymyxin drugs, reflecting not only the severity of drug-resistant bacterial infections but also the importance and potential market value of developing new and safe polymyxin drugs.

Although the use of polymyxins has increased, their inherent toxicity remains a major challenge in clinical application. CATO provides polymyxin impurity reference standards to advance the development of next-generation polymyxin drugs, with the goal of reducing toxicity and improving safety while maintaining antibacterial activity.