Aromatic heptaene macrolides as an initial 'golden shot' towards systemic mycoses

ABSTRACT

Systemic mycoses are fungal diseases attacking the body through an internal organ. They are the cause of increasing morbidity rates, especially among the immunocompromised population (e.g. with HIV), but also exist as a co-infection in patients with COVID-19. Nowadays, the 'life-saving/last chance' drug (and a poison to humans), Amphotericin B (AmB), is the representative of nonaromatic heptaene macrolides. However, previously obtained data indicate significantly higher antifungal activity of the aromatic heptaene subgroup (AHM), which is unfortunately correlated with their high mammalian toxicity. The undertaken studies concern Partricin and Candicidin complexes as the main representatives of AHMs. Three aromatic heptaene macrolides Partricin A, Partricin B and Candicidin D were isolated from fermentation broths of S. aureofaciens and S. griseus, respectively, by initial purification, followed by selected chromatographic techniques such as centrifugal partitioning chromatography (CPC) and prep-HPLC. Later on, they were subjected to controlled chromophore geometry change (cis-trans to all-trans) via photochemical isomerization, using UV light of k = 365 nm. The obtained all-trans isomers, regarded as aromatic analogues of AmB, were tested for in vitro selective toxicity indexes (STIs) towards C. albicans cells versus human erythrocyte model. Due to the diminished hemotoxicity of the all-trans isomers - which were maintaining most of their fungicidal power - the obtained STIs were very promising and far better than for AmB (previously published in J.Górska et al. (2021) Int. J. Mol. Sci. 22). Hence, the all-trans AHMs bear a great potential to be weaponized on the antifungal battlefield. Nevertheless, since individual AHMs are commercially unavailable and difficult to obtain due to their complex nature, our studies will focus on facilitation of the isolation process and further improvement of their STIs, mainly through rational, structural modifications.