br Antibiotic drug discovery approaches Traditionally novel

Antibiotic drug discovery approaches Traditionally, novel latrunculin a synthesis were largely discovered by phenotypic screening approaches of various sources of compounds, such as natural products isolated from extracts of soil microbes and semi-synthetic or fully synthetic compound libraries derived from known antibiotics. To date, target-based in vitro screening approaches have been clearly less successful. However, recently novel approaches have been described that link phenotypical screening with target-centric chemical genomics. Other approaches investigate e.g. untapped natural product sources such as uncultured bacteria for discovering new antibiotics combining high-throughput genome sequencing with high throughput microbial cultivation and synthetic biology.8, 9 This strategy may be especially valuable since it has been estimated that so far less than 1% of all environmental microbes have been cultured in laboratory settings. So far, natural product-screening has undoubtedly been the most productive source for discovering new antibiotics as exemplified by the discovery of the penicillins, cephalosporins, the macrolides such as erythromycin, the glycopeptides such as vancomycin and teicoplanin, the tetracyclines and the aminoglycosides.9, 10 Among antibiotic scaffolds that have emerged recently from natural products, macrocyclic peptides and depsipeptides seem particularly privileged.11, 12, 13, 14, 15 This mini-review will focus mainly on macrocyclic peptide-based scaffolds that led to the discovery of preclinical and clinical stage antibiotics and/or marketed drugs. The vast literature relating to antimicrobial peptides in general has been reviewed elsewhere.16, 17 It is noteworthy, that there are significantly less scaffolds (macrocyclic and non-cyclic) active against Gram-negative bacteria. Lack of membrane permeation of many lipophilic compounds, particularly through the highly negatively charged outer-membrane (OM), seems to be the main problem. In addition, Gram-negative bacteria have efficient efflux pumps and resistance mechanisms. In recent years antibiotics have been discovered that target specifically outer-membrane proteins (OMP’s) in Gram-negative bacteria.
Macrocyclic peptide-based antibiotics against Gram-positive bacteria Table 1 summarizes macrocyclic peptide-based antibiotics classified in compounds that are active mainly on Gram-positive (part 1), both Gram-negative and Gram-positive (part 2), and Gram-negative (part 3) pathogens.
Macrocyclic peptide-based antibiotics against Gram-positive and Gram-negative bacteria
Macrocyclic peptide antibiotics against Gram-negative bacteria As discussed in the introduction, there is currently a particularly high medical need against infections caused by multi-drug resistant Gram-negative ESKAPE pathogens.1, 5
Macrocyclic peptide-based antibiotics in clinical development Several macrocyclic peptide-based antibiotics currently in clinical development are summarized in Table 2. Among the compounds against Gram-negative bacteria, murepavadin (POL7080, Fig. 3b, 29) completed Phase II trials and represents the first member of a new class (OMPTA) of antibiotics. SPR-741 is a polymyxin-derived potentiator which is combined with other antibiotics in Phase I studies. Finally, BSP-804 (structure undisclosed) is again a polymyxin-colistin-derived compound in Phase I. The most advanced compound against Gram-positive bacteria is cefilavancin (TD-1792) (3, Table 1, Fig. 1a), a semi-synthetic glycopeptide-cephalosporin-conjugate which is currently in Phase III for treatment of complicated skin and soft tissues infections. Ramoplanin (NTI-851, Table 1) is a macrocyclic glyco-depsipeptide in Phase II for relapse prevention of Clostridium difficile infections. AeroVanc is a proprietary inhaled dry powder form of vancomycin to treat MRSA lung infections in cystic fibrosis patients. Finally, TD-1607 (4, Fig. 1a) is a different glycopeptide-cephalosporin conjugate and in Phase I for treatment of Gram-positive infections.