Repurposing the Antihistamine Terfenadine for Antimicrobial Activity against Staphylococcus aureus

Abstract

Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure–activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.

In Vitro Screening of an FDA-Approved Library Against ESKAPE Pathogens

“…However, solifenacin succinate, the M3 antagonist, belongs to dihydroisoquinoline antimuscarinics; its chemical structure fits, with high similarity, with the previously identified pharmacophore. Structure-activity relationship (SAR) studies of terfenadine yielded 84 terfenadine-based analogues with improved activity against S. aureus [14]. Terfenadine exerts its antibacterial effect through the inhibition of the bacterial type II topoisomerases [14].…”

“…Structure-activity relationship (SAR) studies of terfenadine yielded 84 terfenadine-based analogues with improved activity against S. aureus [14]. Terfenadine exerts its antibacterial effect through the inhibition of the bacterial type II topoisomerases [14]. …”

An Exploratory Study on the Antimicrobial Activity of Cetirizine Dihydrochloride

“…So, pharmaceutical industries and research organizations are constantly making an effort to synthesize new antibiotics to combat drug resistance. Extensive studies of various workers detect antimicrobial action in different types of drugs belonging to different pharmacological classes, such as antihistamines like bromodiphenhydramine and diphenhydramine [1] , methdilazine [2] , promethazine [3] , trimeprazine [4] , terfenadine [5] , tranquilizers like promazine [6] , antihypertensives like propranolol [7] , methyl dihydroxyphenylalanine (methyl DOPA) [8] , dobutamine [9] , amlodipine [10] , oxyfedrine [11] , lacidipine [12] , antispasmodics like dicyclomine [13,14] , antipsychotics like chlorpromazine [15] , fluphenazine [16] , thioridazine [17] , prochlorperazine [18] , flupenthixol [19] , antiinflammatory agents like diclofenac [20][21][22][23][24] , flurbiprofen [25] and sympathomimetic drug dopamine hydrochloride [26] . Such drugs, having antimicrobial activity in addition to their predesignated pharmacological activity, have been grouped together under the banner of "non-antibiotics" [27] .…”

The Accepted “Clinical Interaction Model”: A Special Case of Reality

“…Antimicrobial activity has been found in many other compounds including flavanones, isoflavones and prenylflavanones [37,38]; antihistamines [39,40], antihypertensive agent methyl-L-DOPA [41]; cardiovascular drugs oxyfedrine and dobutamine [42]; local and general anaesthetics [17,43,44] and barbiturates [45].…”

“…Yes [39,40,[55][56][57][58][59][60][61] Can pathogenicity and virulence be reduced by means of psychotherapeutics and/or other non-antibiotics and their analogues? Yes [62][63][64][65][66] Can the synergy between psychotherapeutics and "classical" antibiotics/chemotherapeutics be expoited (for example to reduce the dose)?…”