Cyclic Lipodepsipeptides: A New Class of Antibacterial Agents in the Battle Against Resistant Bacteria

Abstract

In order to provide effective treatment options for infections caused by multidrug-resistant bacteria, innovative antibiotics are necessary, preferably with novel modes of action and/or belonging to novel classes of drugs. Naturally occurring cyclic lipodepsipeptides, which contain one or more ester bonds along with the amide bonds, have emerged as promising candidates for the development of new antibiotics. Some of these natural products are either already marketed or in advanced stages of clinical development. However, despite the progress in the development of new antibacterial agents, it is inevitable that resistant strains of bacteria will emerge in response to the widespread use of a particular antibiotic and limit its lifetime. Therefore, development of new antibiotics remains our most efficient way to counteract bacterial resistance.

The action mechanism of daptomycin

“…Furthermore, in 2006, approval was given for treatment of bacteraemia and right-sided endocarditis caused by MSSA and MRSA. 3 Although many cyclic lipopeptide antibiotics have been discovered, 4,5 daptomycin remains the only member of this class that is approved for clinical use.…”

“…They essentially found no preferred structure. A model of the structure closest to the ensemble average shows the backbone forming two bends at Asp (7) and Asp (9) , with a highly variable region around Gly (5) (see Figure 4B). …”

“…Asp (5) Asp (7) B D-Asp (2) Asp (7) Asp (9) mGlu (12) Figure 4: Crystal structure of tsushimycin, 46 and NMR structure of daptomycin. 42 A: In tsushimycin, Ca 2+ is coordinated by Asp (5) together with several backbone carbonyls from the ring. Additional calcium ions that bridge adjoining tsushimycin molecules in the crystal are not shown.…”

“…46 The peptide backbone resembles a saddle with a long tail. A Ca 2+ ion is bound in the middle of the saddle by interaction with the side-chains of two Asp groups (Asp (1) and Asp (5) ), four backbone carbonyl O atoms (Dab (2) , Gly (6) , Gly (8) and Val (10) ), and a water molecule (see Figure 4A). …”

“…Readers interested in learning more about these topics are referred to several previous reviews. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] …”