Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of γ-actinorhodin

Abstract

Of the thousands of natural product antibiotics discovered to date, only a handful have been developed for the treatment of bacterial infection. The clinically unexploited majority likely include compounds with untapped potential as antibacterial drugs, and in view of the ever-growing unmet medical need for such agents, warrant systematic re-evaluation. Here we revisit the actinorhodins, a class that was first reported 70 years ago, but which remains poorly characterized. We show that γ-actinorhodin possesses many of the requisite properties of an antibacterial drug, displaying potent and selective bactericidal activity against key Gram-positive pathogens (including Staphylococcus aureus and enterococci), a mode of action distinct from that of other agents in clinical use, an extremely low potential for the development of resistance, and a degree of in vivo efficacy in an invertebrate model of infection. Our findings underscore the utility of revisiting unexploited antibiotics as a source of novel antibacterial drug candidates.

Unique secondary metabolites of a Streptomyces strain isolated from extreme salty wetland show antioxidant and antibacterial activities

“…As expected, most of the compounds identified in the chemical analysis were reported before as secondary metabolites of Streptomyces , such as naringenin, the aglycone of narirutin (Álvarez‐Álvarez et al ), γ ‐actinorhodin (Nass et al ), germicidins (Čihák et al ), geldanamycin (Fukuyo et al ), doxorubicin (Arcamone et al ), 4,5‐dihydrogeldanamycin (Lin et al ), albaflavenone (Lin and Cane ; Čihák et al ), lasalocid (Shichijo et al ), antimycin B2 (Han et al ), linearolide A (Ueki et al ) and ascomycin (Griffiths ). Interestingly, to our knowledge, genistein‐7‐ O ‐glucuronide, phenyl acetic acid, 7,3’,4’‐trihydroxyflavanone, resveratrol and mycophenolic acid have never been reported before in Streptomyces .…”

“…In addition, several compounds identified in the extract have been associated in the literature with antibacterial activity. So, γ ‐actinorhodin (Nass et al ), geldanamycin (Shin et al ), doxorubicin (Arcamone et al ), mycophenolic acid (Merrigan et al ), germicidin A and germicidin analogous (Petersen et al ; Čihák et al ), albaflavenone (Lin and cane ; Čihák et al ) and antimycin B2 (Han et al ) are likely to be the compounds responsible for the antibacterial activity reported in this study. Interestingly, some of the identified compounds have been associated with activities that can be considered very important for human applications.…”

“…According to the chemical analysis, the crude extract of Streptomyces AR2 contains germicidins and γ ‐actinorhodin (Table ) that were reported in the literature as selective bactericidal against Gram‐positive pathogens, including B. subtilis (the case of germicidin; Čihák et al ) and S. aureus (the case of γ ‐actinorhodin; Nass et al ). Therefore, it is reasonable to conclude that the antibacterial activity of AR2 extract is mainly directed against Gram‐positive bacteria.…”

Identification and Testing of Antidermatophytic Oxaborole-6-Benzene Sulphonamide Derivative (OXBS) from Streptomyces atrovirens KM192347 Isolated from Soil

“…Streptomyces spp. is considered to be the major producers of about half of all naturally occurring antibiotics [3]. Streptomyces spp.…”

Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance

“…Another promising strategy for combating antibiotic resistance is to resurrect discarded antibiotics by reducing undesired side-effects and improving target affinity (Maviglia, Nestorini, & Pennisi, 2009;Nass et al, 2017). Synthesizing prodrug versions of an antibiotic is one confirmed method for masking activity or shifting toxicity (Blondiaux et al, 2017;Istvan et al, 2017;Pires et al, 2015).…”