Design and Synthesis of Potent Sensitizers of Gram-Negative Bacteria Based on a Cholic Acid Scaffolding

• Published in: Journal of the American Chemical Society 1998-04, Vol.120 (12), p.2961-2962
• Main Authors: Li, Chunhong, Peters, Adam S, Meredith, Erik L, Allman, Glenn W, Savage, Paul B
• Format: Article
• Language: English
• Subjects: lipid A; sensitizers
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja973881r

The outer membrane of Gram-negative bacteria provides a protective barrier against proteases, lysozymes, and many types of antibiotics. Consequently, numerous antibiotics that are active against Gram-positive bacteria are much less active against Gram-negative strains. Lipid A is a primary component of the outer membrane of Gram-negative bacteria and plays an essential role in cell wall integrity. Compounds known to associate strongly with lipid A disrupt the organization of the outer cell wall and thereby sensitize Gram-negative bacteria to antibiotics. These compounds have generally been derivatives of polymyxin B (1, Figure 1), the most common member of a family of related peptide antibiotics. Derivatives of polymyxin B such as polymyxin B nonapeptide (2, Figure 1), and polymyxin B heptapeptide (3, Figure 1) sensitize bacteria to antibiotics without causing toxic effects that limit the use of polymyxin B. However, compounds such as 2 and 3 are difficult to prepare and purify. We have prepared simple, nonpeptide mimics of polymyxin B that act as potent sensitizers of Gram-negative bacteria to antibiotics. Design of the new sensitizers was based upon modeling of the lipid A binding domain of polymyxin B and consideration of the conserved residues found in polymyxin B and related antibiotics. Through the pioneering work of Vaara and co-workers, the lipid A binding domain of polymyxin B has been identified as the macrocyclic portion of the molecule (3). Molecular modeling of 3 with constraints derived from reported NOESY experiments and predicted peptide turn formation provided a low-energy structure in which the three amine groups derived from diaminobutyric acid residues are oriented on one face of the molecule (Figure 2). Since these diaminobutyric acid groups are conserved among the related antibiotics polymyxins A, B sub(1), B sub(2), D sub(1), E sub(1), and E sub(2), circulin A, and octapeptins A sub(1), A sub(2), A sub(3), B sub(1), B sub(2), B sub(3), and C sub(1), we included three primary amines in the design of our sensitizers. The fact that simple polyamines and linear versions of 3 do not sensitize Gram-negative bacteria to antibiotics suggests that a specific arrangement of amine groups is required for sensitization activity. Our modeling demonstrated that appropriate functionalization of cholic acid results in orientation of three amine groups in a conformation comparable to that predicted for 3 (Figure 2). Our hypothesis was that if associat