Chemical Synthesis and Structure-Activity Relationship Study Yield Desotamide a Analogues with Improved Antibacterial Activity.

Run Xu,Qinglian Li,Jun Li,Jianhua Ju,Yongxiang Song

doi:10.3390/md19060303

Abstract

Desotamides A, a cyclohexapeptide produced by the deep-sea-derived Streptomyces scopuliridis SCSIO ZJ46, displays notable antibacterial activities against strains of Streptococcus pnuemoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus epidermidis (MRSE). In this study, to further explore its antibacterial potential and reveal the antibacterial structure-activity relationship of desotamides, 13 cyclopeptides including 10 new synthetic desotamide A analogues and wollamides B/B1/B2 were synthesized and evaluated for their antibacterial activities against a panel of Gram-positive and -negative pathogens. The bioactivity data reveal that residues at position II and VI greatly impact antibacterial activity. The most potent antibacterial analogues are desotamide A4 (13) and A6 (15) where l-allo-Ile at position II was substituted with l-Ile and Gly at position VI was simultaneously replaced by d-Lys or d-Arg; desotamides A4 (13) and A6 (15) showed a 2–4-fold increase of antibacterial activities against a series of Gram-positive pathogens including the prevalent clinical drug-resistant pathogen methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 8–32 μg/mL compared to the original desotamide A. The enhanced antibacterial activity, broad antibacterial spectrum of desotamides A4 and A6 highlighted their potential as new antibiotic leads for further development.

Highlights

Bacterial infection has always been an urgent threat to human health care, and this threat is worsening by the rapid emergence and spread of antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus, as well as the multidrug-resistantGram-negative bacteria [1,2,3]
To further investigate the structure-activity relationship (SAR) and explore the potential of desotamide A (1) as candidates of antibacterial drug development, we report the synthesis of 10 new desotamide A analogues (10–19) and their antibacterial properties
Desotamides A and B displayed antibacterial activities that were not seen with desotamides C and D [12], revealing that the Trp moiety at position V is essential for antibacterial activity

Summary

Introduction

Bacterial infection has always been an urgent threat to human health care, and this threat is worsening by the rapid emergence and spread of antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus, as well as the multidrug-resistantGram-negative bacteria [1,2,3]. Bacterial infection has always been an urgent threat to human health care, and this threat is worsening by the rapid emergence and spread of antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus, as well as the multidrug-resistant. Despite a growing clinic need, the discovery of antibiotics for treatments of bacterial infections slowed dramatically, with a limited number of new scaffolds marketed in the past forty years [5]. There is an urgent need to continuously search for new classes of antibiotics with novel mechanisms of action to combat the growing antibiotic resistance. Natural products of microbial origin are privileged in the sphere of antibiotic development and underpin the majority of antibiotics in clinical use [6,7,8]. The cyclic hexapeptides desotamides represent one of such class of cyclopeptides. Desotamides A–D are produced by the deep-sea-derived

Methods

Results

Conclusion