Antibiofilm activity of manogepix, ibrexafungerp, amphotericin B, rezafungin, and caspofungin against <i>Candida</i> spp. biofilms of reference and clinical strains

This study comprehensively assessed the activity of manogepix (MNGX), ibrexafungerp (IBF), amphotericin B (AMB), rezafungin (RZF), and caspofungin (CAS) against planktonic cells and mature biofilms of <i>Candida</i> spp.-reference and clinical strains using the Calgary biofilm device. Mature-phase biofilms of <i>C. albicans</i>, <i>C. auris (clades I, II, III, IV</i>), and <i>C. parapsilosis</i> were exposed to a range of drug concentrations (0.12-128 µg/mL). Minimum Inhibitory Concentration (MIC) values for planktonic cells were ≤2 µg/mL for all strains; however, biofilm-associated MICs, minimum biocidal concentration (MBC), minimum biofilm eradication (MBEC), and minimum biofilm damaging concentration (MBDC) were significantly higher (2-4,119 times). Geometric mean (GM) of MBEC values indicated that MNGX had the highest antifungal activity within <i>Candida</i> species, with a GM-MBEC of 5.9 µg/mL. Despite its overall potency, MNGX was less effective against <i>C. auris</i> biofilms from clade IV strains, where IBF showed superior activity. While not the most potent agent overall, AMB induced the smallest fold-change increases (2- to 32-fold) in biofilm-associated states data compared to planktonic MICs. Conversely, CAS exhibited the lowest activity against <i>Candida</i> spp. biofilms. The eradication of <i>C. auris</i> and <i>C. parapsilosis</i> biofilms required substantially higher concentrations than <i>C. albicans</i>, with some agents, such as RZF and CAS, necessitating up to 42-fold increases in dosage. In conclusion, our <i>in vitro</i> model highlights the antibiofilm activity of novel antifungals against major <i>Candida</i> species, revealing significant differences in efficacy among species. MNGX demonstrated the highest activity, underscoring its potential as a promising candidate for the treatment of biofilm-related infections.