From Antihistamine to Anti-infective: Loratadine Inhibition of Regulatory PASTA Kinases in Staphylococci Reduces Biofilm Formation and Potentiates β-Lactam Antibiotics and Vancomycin in Resistant Strains of Staphylococcus aureus

Abstract

Staphylococcus epidermidis and Staphylococcus aureus are important human pathogens responsible for two-thirds of all postsurgical infections of indwelling medical devices. Staphylococci form robust biofilms that provide a reservoir for chronic infection, and antibioticresistant isolates are increasingly common in both healthcare and community settings. Novel treatments that can simultaneously inhibit biofilm formation and antibiotic-resistance pathways are urgently needed to combat the increasing rates of antibiotic-resistant infections. Herein we report that loratadine, an FDA-approved antihistamine, significantly inhibits biofilm formation in both S. aureus and S. epidermidis. Furthermore, loratadine potentiates β-lactam antibiotics in methicillin-resistant strains of S. aureus and potentiates both β-lactam antibiotics and vancomycin in vancomycin-resistant strains of S. aureus. Additionally, we elucidate loratadine's mechanism of action as a novel inhibitor of the regulatory PASTA kinases Stk and Stk1 in S. epidermidis and S. aureus, respectively. Finally, we describe how Stk1 inhibition affects the expression of genes involved in both biofilm formation and antibiotic resistance in S. epidermidis and S. aureus.

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

“…A small-molecule quinazoline compound (Inh2-B1) inhibited specifically Stk1 in S. aureus. It reduced MBCs of ceftriaxone and cefotaxime for MRSA from ≥ 100 to ≤ 4 mg/L [100]. The finding that loratadine resensitized MRSA to vancomycin [99] is in contrast to previous reports [83][84][85] that STPK inhibitors revert activities of β-lactams only but not other antibiotic classes.…”

Evaluation of small molecule kinase inhibitors as novel antimicrobial and antibiofilm agents

“…Our group observed similar effects on biofilm formation and dispersion when we evaluated loratadine (49) (Cutrona et al, 2019). Loratadine was capable inhibiting biofilm formation in MSSA, MRSA, and VRSA strains with MBIC 50 values ranging from 11.49 ± 2.54 to 59.90 ± 1.29 μM.…”

“…Stk1 (PknB) (Cutrona et al, 2019;Greco et al, 2020;Kant et al, 2017;Schaenzer et al, 2018) 45 (Schaenzer et al, 2018), 46 (Greco et al, 2020), 47 (Greco et al, 2020), 48 (Kant et al, 2017), 49 (Cutrona et al, 2019) Streptococcus mutans PknB (Banu et al, 2010;Hussain et al, 2006)…”

“…Recently, our own group disclosed the discovery that loratadine (49, Figure 5), the active ingredient in Claritin®, was capable of inhibiting Stk1 in S. aureus (Cutrona et al, 2019). Loratadine was able to potentiate βlactam antibiotics in both hospital-acquired (HA) and communityacquired (CA) strains of MRSA.…”

A smart hydrogel for on-demand delivery of antibiotics and efficient eradication of biofilms

“…Nanomedicines and biomaterials have shown great promise in the treatment of various diseases in recent years [17][18][19][20]. To treat biofilm-associated infections, quorum sensing inhibitors [21,22], nanoparticles [23][24][25], antimicrobial peptides [26], antisense nucleic acids [27,28], enzyme mimetics [29], polymers [30][31][32] and antifouling coatings [33][34][35][36] with the activity of inhibiting biofilm formation were developed in the past decade. These compounds or materials could sensitize biofilm infections to conventional antibiotics [6,37].…”