Intracellular efflux pumps have been largely the research focus in multidrug-resistant (MDR) Gram-positive and Gram-negative microorganisms and parasites including cancers. However, drug efflux mechanisms other than pumps per se have been observed, supported by the effects of isomeric, non-antibiotic depressant (DPR), phenothiazines and thixenes, and antidepressant (ADPR) phenylpiperidine neurotropic drugs, alone or in combination with classical antimicrobials on MDR Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes and Streptococcus pneumoniae. Of the non-antibiotics we investigated, the DPR l-thioridazine, trans-clopenthixol and isomers of phenylpiperidines NNC 20-4962 (isomer of femoxetine) and NNC 20-7052 (isomer of paroxetine) were potent antimicrobials with the least neurotropic activity, pointing to a possible general isomeric structure-activity relationship. These compounds may be regarded as new efflux inhibitors. Moreover, these isomers have considerably reduced, in some cases absent, neurotropism and reduced mammalian toxicity. This may alleviate concerns about adverse effects and therapeutic safety for infected patients in life-threatening situations where the non-antibiotic dosage would be in the lower, non-chronic dosage ranges generally prescribed for individuals with mild mental health problems. The results point to the prokaryotic and eukaryotic microorganisms' phospholipid/protein domain involvement of the cationic, amphiphilic, non-antibiotic DPR and ADPR, with the phospholipids being the initial sites attracting and concentrating the neurotropes to induce a form of suspended animation, followed by gross changes of cell wall and membrane structure, and thereby potentiating their destructive or immobilizing effects on various as yet only hinted at resistance and efflux mechanisms. Combination of appropriate isomeric non-antibiotic DPR and ADPR of low neurotropism and toxicity with conventional and classical antimicrobials promises early, new therapeutic strategies salutary against microbial resistance, resistance development, pathogenicity and virulence.
Abstract:The antimicrobial activity of the phenothiazine derivatives thioridazine and prochlorperazine have been evaluated with 11 Enterococcus faecalis strains and 9 Enterococcus faecium strains, originating from human infections and animal faecal flora. We found that all E. faecalis and E. faecium strains, regardless of their susceptibility to commonly used antibiotics, were inhibited by thioridazine at a concentration of 16-32 mg/ml and by prochlorperazine at a concentration of 32-64 mg/ ml. Combinations of the antibiotics vancomycin or ampicillin and thioridazine and prochlorperazine at subinhibitory concentrations, could render vancomycin-or ampicillin-resistant bacteria sensitive to each of the antibiotics. Verapamil and reserpine, inhibitors of P-glycoprotein-mediated multidrug resistance, did not reduce resistance. Our results outline modification of resistance in enterococci induced by phenothiazine derivatives unrelated to P-glycoprotein-mediated multidrug resistance.
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