Abstract
Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway among various strategies to prevent resistance. Guanidine-containing polyhydroxyl macrolides, containing a polyhydroxyl lactone ring and a guanidyl side chain, can be produced by many actinomycetes and have been proved to possess many bioactivities, especially broad-spectrum antibacterial and antifungal activities. To explore the potential of these compounds to be developed into new antimicrobial agents, a review on their structural diversities, spectroscopic characterizations, bioactivities, acute toxicities, antimicrobial mechanisms, and the structure-activity relationship was first performed based on the summaries and analyses of related publications from 1959 to 2019. A total of 63 guanidine-containing polyhydroxyl macrolides were reported, including 46 prototype compounds isolated from 33 marine and terrestrial actinomycetes and 17 structural derivatives. Combining with their antimicrobial mechanisms, structure-activity relationship analyses indicated that the terminal guanidine group and lactone ring of these compounds are vital for their antibacterial and antifungal activities. Further, based on their bioactivities and toxicity analyses, the discovery of guanidyl side-chain targeting to lipoteichoic acid of Staphylococcus aureus indicated that these compounds have a great potency to be developed into antimicrobial and anti-inflammatory drugs.
Highlights
Antimicrobial resistance has become a serious threat to human health and economic development [1]
Inspired by the fact that the antimicrobial activities of azalomycin F and copiamycin could be reversed in the same manner by the phospholipid fraction of the bacteria, and various phospholipids, such as phosphatidylglycerol (PG) and phosphatidylcholine [89], Yuan et al [26] discovered that azalomycin F5a, the main component of azalomycin F, could lead to the leakage of cellular substances possibly by increasing permeability to kill S. aureus and confirmed that cell-membrane lipids, especially 1,2-dihexadecanoyl-sn-glycero-3-phospho-(10 -rac-glycerol) (DPPG), might be important targets of azalomycin F5a against S. aureus after its relative configurations were assigned [24,26]
Thereby, molecular dynamics simulation, showing that azalomycin F5a had greater adhesive force to plasma membrane assembled by DPPG plus lysyl-DPPG than by DPPG, indicated that azalomycin F5a likely had greatly antagonistic activity to daptomycin-resistant S. aureus strains, and proposed that these compounds had a great potency to be developed into new antimicrobial agents as lipoteichoic acid (LTA) is an important target for new antibiotics [92,93]
Summary
Antimicrobial resistance has become a serious threat to human health and economic development [1]. Until 2013, the relative configurations of azalomycins F5a , F4a , and F3a as three representatives of these compounds, together with seven new analogs, were reported by Yuan et al [24,25]. These compounds have broad-spectrum antimicrobial activity (especially Gram-positive bacteria and fungi) [31,32,33], anti-trichomonas [34], cytotoxicity [31,32], and so on. Along with the clarification of some antimicrobial mechanisms and structure-activity relationships, we here presented a review on the chemistry and biology of these compounds discovered from 1959 to 2019 for exploring their potential in drug development
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