Abstract
The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing mycobacterial resistance. An alternative to such novel drugs or combined therapeutic regimes which may reduce resistance development is finding enhancers of mycobacterial drug effectiveness, especially enhancers that counteract causative resistance mechanisms. Such enhancers may reduce the extracellular drug efflux mediated by bacterial efflux pumps and thus enhance the intracellular drug toxicity. We developed novel 1,4-dihydropyridines (DHPs) as potential efflux pump inhibitors with some determined P-gp affinities. The influence on the antituberculotic drug toxicity has been investigated for three prominent antituberculotic drugs. Exclusive and selective toxicity enhancing effects have been detected for isoniazid (INH) which could be related to certain substituent effects of the 1,4-DHPs. So, structure-dependent activities have been found. Thus, promising enhancers could be identified and a suggested efflux pump inhibition is discussed.
Highlights
The most recent tuberculosis (Tb) report of the World Health Organization (WHO) states that TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS
The lower yields may be caused by a reduced nucleophilic activity of the aniline nitrogen compared to that of ammonia used for the synthesis of the clinically used 1,4-dihydropyridines without a nitrogen substituent and higher isolated yields varying from the reaction conditions [10,11]
As we observed a specific drug toxicity enhancing effect for INH when combined with our novel compounds, we wondered whether the used subinhibitory concentration of INH might have induced an efflux pump sensitive to our compounds as potential inhibitors
Summary
The most recent tuberculosis (Tb) report of the World Health Organization (WHO) states that TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. MDR-TB (multidrug-resistant tuberculosis) [3] In such a case, second-line antibiotics are used in a combined regime of four or five drugs including fluoroquinolone and aminoglycoside compounds [3]. Very few established drugs have been investigated to increase the intracellular toxicity of antituberculotic drugs All of those used drugs have pharmacological activities like phenothiazines, verapamil, or reserpine which make them toxic for the use as potential enhancers of the antituberculotic drug activity by the inhibition of the extracellular efflux [8]. The compounds’ P-gp activities cannot be related to any activity data determined in Mtb because P-gp as an efflux pump is not present in Mtb. The novel compound class could be profiled in the use of the three most prominent antituberculotic drugs INH, RIF, and EMB with exclusive and selective effects on the INH toxicity which is discussed in relation to substituent effects
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