Abstract
In the current study forty eight compounds belonging to anthraquinones, naphthoquinones, benzoquinones, flavonoids (chalcones and polymethoxylated flavones) and diterpenoids (clerodanes and kauranes) were explored for their antimicrobial potential against a panel of sensitive and multi-drug resistant Gram-negative and Gram-positive bacteria. The minimal inhibitory concentration (MIC) determinations on the tested bacteria were conducted using modified rapid INT colorimetric assay. To evaluate the role of efflux pumps in the susceptibility of Gram-negative bacteria to the most active compounds, they were tested in the presence of phenylalanine arginine β-naphthylamide (PAβN) (at 30 µg/mL) against selected multidrug resistance (MDR) bacteria. The anthraquinone, emodin, naphthaquinone, plumbagin and the benzoquinone, rapanone were active against methicillin resistant Staphylococcus aureus (MRSA) strains of bacteria with MIC values ranging from 2 to 128 μg/mL. The structure activity relationships of benzoquinones against the MDR Gram-negative phenotype showed antibacterial activities increasing with increase in side chain length. In the chalcone series the presence of a hydroxyl group at C3′ together with a methoxy group and a second hydroxyl group in meta orientation in ring B of the chalcone skeleton appeared to be necessary for minimal activities against MRSA. In most cases, the optimal potential of the active compounds were not attained as they were extruded by bacterial efflux pumps. However, the presence of the PAβN significantly increased the antibacterial activities of emodin against Gram-negative MDR E. coli AG102, 100ATet; K. pneumoniae KP55 and KP63 by >4–64 g/mL. The antibacterial activities were substantially enhanced and were higher than those of the standard drug, chloramphenicol. These data clearly demonstrate that the active compounds, having the necessary pharmacophores for antibacterial activities, including some quinones and chalcones are substrates of bacterial efflux pumps and therefore should be combined to efflux pump inhibitors in the fight against MDR bacterial infections.
Highlights
Multidrug resistance (MDR) in bacteria is usually mediated by the expression of efflux pumps or porins involved in transport, by the expression of mutated genes coding for specific drug targets or specific enzymatic barriers
The results show that the anthraquinone (2), naphthaquinone, plumbagin (5) benzoquinones (11, 12, 17, 18), chalcones (19, 21) were active against methicillin resistant Staphylococcus aureus (MRSA) bacteria strains with minimal inhibitory concentration (MIC) value ranging from 2 to 128 μg/ mL
Structure activity relationships of benzoquinones; which has not been carried out in previous studies, showed that antibacterial activities gradually increased with increasing side chain length from 2, 3, 4 for 6, 7 and 8, respectively, with optimal activities being realized with C7 (9)
Summary
Multidrug resistance (MDR) in bacteria is usually mediated by the expression of efflux pumps or porins involved in transport, by the expression of mutated genes coding for specific drug targets or specific enzymatic barriers. One way of tackling the emergence of MDR is to diversify the chemical structures of anti-microbial drugs to which resistance has developed in order to extend their lifespan (De Clercq 2001; Poole 2001; Jeu et al 2003). The compounds exhibiting modest to significant antibacterial activities against MDR phenotypes, could be used in combination with the efflux inhibitors, in order to improve on the accumulation of the drug in the cells for optimal activities (Kuete et al 2011). It is not surprising that in response to anti-microbial resistance, major pharmaceutical companies have concentrated their efforts on improving chemotherapeutic agents in established drug classes (Taylor et al 2002). The compounds of interest for the development of novel drugs include those that target different proteins or biochemical processes compared to those in current use and those that inhibit bacterial efflux pumps (Kuete et al 2011). The chemical moieties relevant for pharmacophore binding were analyzed by their structure activity relationships (SAR) studies of related compounds
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