Polymyxin B as scaffold for new analogues bearing uncommon amino acids: synthesis and antibiotic activity

• Author(s): Linhares, Mariana ; Lopes, Susana Patrícia ; Costa, Susana P.
• Date: 2025
• Persistent ID: https://hdl.handle.net/1822/98397
• Origin: RepositóriUM - Universidade do Minho
• Document Type: Conference poster
• Language: English
• Contributor(s): Universidade do Minho

Description

The alarming rise of antimicrobial resistance (AMR) and multidrug-resistant (MDR) Gram-negative bacteria led the World Health Organization (WHO) to publish a list of pathogens for which the development of new antibiotics is urgent. Some bacteria have been prioritized as they are resistant to more than three classes of antibiotics, such as the ESKAPE group that includes Gram-positive bacteria (Enterococcus faecium, Staphylococcus aureus) and Gram-negative bacteria (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). In addition to multiresistance, they present increasing levels of virulence, which make these bacteria essentially responsible for infections in hospital environments [1,2]. The dry antibiotic pipeline is not able to keep pace to address this problem, and polymyxins (PMs) have recently been rehabilitated as last-resort drugs against MDR Gram-negative bacteria. Regrettably, besides the well-documented side effects (nephro- and neurotoxicity), resistance has also emerged in response to their increased use [3]. This has triggered the search for new PM derivatives with improved activity and reduced toxicity. However, the study of a large number of modified PMs has not yet outputted a better performing derivative. Bearing this in mind, we now present the synthesis of polymyxin B (PMB) analogues through modification at selected positions, with structurally related uncommon amino acids, considering previous structure-activity relationship studies. The synthesised analogues were evaluated for their antimicrobial activity by determining the minimum inhibitory concentration and minimum bactericidal concentration against planktonic cultures of Gram-negative (P. aeruginosa) and Gram-positive (S. aureus) strains. Their antimicrobial effect was compared with that obtained by the commercial PMB.