Repurposing Kinase Inhibitor Bay 11-7085 to Combat Staphylococcus aureus and Candida albicans Biofilms

Abstract

Staphylococcus aureus and Candida spp. are commonly linked with topical biofilm-associated infections such as those found on chronic wounds. These biofilms are notoriously difficult to treat, highlighting the grave need to discover and study new broad-spectrum agents to combat associated infections. Here we report that the kinase inhibitor Bay 11-7085 exhibited bactericidal activity against multidrug-resistant S. aureus with a minimum inhibitory concentration (MIC) of 4 μg/ml. In addition, S. aureus strain MW2 did not acquire resistance to antibiotic pressure. Furthermore, Bay 11-7085 exhibited potency against Candida albicans and the emerging pathogen Candida auris with a MIC of 0.5–1 μg/ml. Bay 11-7085 partially inhibited and eradicated biofilm formation of various pathogens, such as VRSA (vancomycin-resistant S. aureus), as well as antifungal-resistant Candida spp. isolates. Notably, Bay 11-7085 partially inhibited initial cell attachment and formation of a VRSA-C. albicans polymicrobial biofilm in vitro. In contrast to C. albicans, inhibition of VRSA biofilm was linked to initial cell attachment independent of its bactericidal activity. Finally, Bay 11-7085 was effective in vivo at increasing the lifespan of C. elegans during an S. aureus and a C. albicans infection. Our work proposes kinase inhibitor Bay 11-7085 as a potential compound capable of combating biofilms associated with primary multidrug-resistant bacteria and yeast pathogens associated with wound infections.

Recent Advances and Opportunities in the Study of Candida albicans Polymicrobial Biofilms

“…This compound was also recently shown to be able to inhibit C. albicans-S. aureus biofilms (She et al, 2020). Bay 11-7085 is another small molecule with possible antibacterial activity that could prevent formation of C. albicans-S. aureus biofilms, by inhibiting initial attachment and biofilm growth, especially of C. albicans (Escobar et al, 2021).…”

Exploration of BAY 11-7082 as a Potential Antibiotic

“…While all analogues retain the nitrile group, some have a pyridine instead of a pyrazine (33,34) to assess the effect of alternate heterocycles on activity. Capitalizing on our success with the fluorine analogue 5, we designed analogues with halogen substituents at the para position of the benzene (24,25,28,33,34), as well as 30 with a meta-fluorine, three analogues with two fluorine substituents at differing positions (27,31,32), and 26 with a para-trifluoromethyl group. We also explored a nitrile group (29) as an example of a nonhalogen para electron-withdrawing substituent.…”

Exploration of BAY 11-7082 as a novel antibiotic

“…BAY 11-7085 6, another anti-inflammatory and structural analogue of BAY 11-7082, was recently identified as an antimicrobial with activity against S. aureus and Candida albicans. 34 S. aureus contains two low molecular weight PTPs, PtpA and PtpB, both of unknown function. 36 We also considered the TAT system as a target, as BAY 11-7082 was previously identified as a P. aeruginosa TAT inhibitor, where it was also suggested to bind a nucleophilic cysteine.…”

“…PSPC differs from BAY 11-7082 by the addition of a pyrazine between the sulfone and the nitrile. While all analogues retain the nitrile group, some have a pyridine instead of a pyrazine (33,34). Capitalizing on our success with the fluorine analogue 5, we designed analogues with halogen substituents at the para position of the benzene (24, 25, 28, 33, 34), as well as with a meta fluorine, three analogues with two fluorine substituents at differing positions (27,31,32), and 26 with a para trifluoromethyl group.…”