Resensitization of methicillin-resistant Staphylococcus aureus by amoxapine, an FDA-approved antidepressant

Abstract

The rapid increase in bacterial resistance to antibiotics is a global healthcare crisis. Non-antibiotic pharmaceuticals that have attained approval by the United States Food and Drug Administration have the potential to be repurposed as bacterial resistance-modifying agents and therefore could become valuable resources in our battle against antibiotic-resistant microbes. Amoxapine is a tetracyclic antidepressant used in the treatment of major depressive disorder. Here we demonstrate the ability of amoxapine to resensitize methicillin-resistant Staphylococcus aureus strain ATCC 43300 to oxacillin in both agar diffusion and broth microdilution assays. Amoxapine also reduced the bacterial cleavage of nitrocefin in a dose-dependent manner, suggesting that it may exert its adjuvant effects through reduction of beta-lactamase activity.

Keywords: Microbiology.

Fig. 1

Growth of S. aureus is not completely inhibited by amoxapine. (A) Chemical structure of amoxapine, CAS 14028-44-5. (B) Optical densities (OD₆₀₀) of 3 mL S. aureus cultures after 16–18 h of incubation at 37 °C with shaking at 180 rpm in the presence of amoxapine. Culture densities are expressed as a percentage of the DMSO control. The mean of 4 technical replicates collected from 2 independent experiments is shown. Error bars represent SEM. * indicates p < 0.05 vs DMSO control.

Fig. 2

Effects of amoxapine on oxacillin disc-diffusion sensitivity and nitrocefin cleavage. (A) Zones of inhibited methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) growth by oxacillin. MHII agar plates contained either 1% DMSO (blue bars) or 300 μM amoxapine (red bars). For MSSA, the mean of 3 technical replicates collected from a single experiments is shown. For MRSA, the mean of 5 technical replicates collected from 2 independent experiments is shown. (B) Following a pretreatment with oxacillin to increase β-lactamase production, washed cultures of MRSA were incubated at 37 °C in the presence of amoxapine and nitrocefin, a chromogenic β-lactamase substrate in a 96-well microtiter plate. Absorbance of the cultures at 486 nm was monitored for a period of 2 h. The change in absorbance at 486 nm is expressed as a percentage of the oxacillin-induced DMSO control. The mean of 4 independent biological replicates, each performed with 5 technical replicates, is shown. Error bars represent SEM. * indicates p < 0.05 vs DMSO control.