Holarrhena antidysenterica has been employed as an ethnobotanical plant for the treatment of dysentery, diarrhoea, fever, and bacterial infections. Biological activities of the principle compound, conessine including anti-diarrhoea and anti-plasmodial effects were documented. Our previous study reported potency of Holarrhena antidysenterica extract and conessine as resistance modifying agents against extensively drug-resistant Acinetobacter baumannii. This study aimed to investigate (i) whether conessine, a steroidal alkaloid compound, could act as a resistance modifying agent against multidrug-resistant Pseudomonas aeruginosa, and (ii) whether MexAB-OprM efflux pump involved in the mechanism. Conessine combined with various antibiotics were determined for synergistic activity against P. aeruginosa PAO1 strain K767 (wild-type), K1455 (MexAB-OprM overexpressed), and K1523 (MexB deletion). H33342 accumulation assay was used to evaluate efflux pump inhibition while NPN uptake assay was assessed membrane permeabilization. Conessine significantly reduced MICs of all antibiotics by at least 8-fold in MexAB-OprM overexpressed strain. The levels were comparable to those obtained in wild-type strain for cefotaxime, levofloxacin, and tetracycline. With erythromycin, novobiocin, and rifampicin, MICs were 4- to 8-fold less than MICs of the wild-type strain. Loss of MexAB-OprM due to deletion of mexB affected susceptibility to almost all antibiotics, except novobiocin. Synergistic activities between other antibiotics (except novobiocin) and conessine observed in MexB deletion strain suggested that conessine might inhibit other efflux systems present in P. aeruginosa. Inhibition of H33342 efflux in the tested strains clearly demonstrated that conessine inhibited MexAB-OprM pump. In contrast, the mode of action as a membrane permeabilizer was not observed after treatment with conessine as evidenced by no accumulation of 1-N-phenylnaphthylamine. The results suggested that conessine could be applied as a novel efflux pump inhibitor to restore antibiotic activity by inhibiting efflux pump systems in P. aeruginosa. The findings speculated that conessine may also have a potential to be active against homologous resistance–nodulation–division (RND) family in other Gram-negative pathogens.

Chemotherapy is a vital option for cancer treatment; however, its therapeutic outcomes are limited by dose-dependent toxicity and the occurrence of chemoresistance. siRNAs have emerged as an attractive therapeutic option enabling specific interference with target genes. Combination therapy using chemotherapeutic agents along with gene therapy could be a potential strategy for cancer management, which not only improves therapeutic efficacy but also decreases untoward effects from dose reduction. In this study, a cationic niosome containing plier-like cationic lipid B was used to convey siRNA against anti-apoptotic mRNA into MCF-7 and MDA-MB-231 cells. Mcl-1 silencing markedly decreased the viability of MCF-7 cells and triggered apoptosis. Moreover, computer modeling suggested that the combination of doxorubicin (Dox) and Mcl-1 siRNA exhibited a synergistic relationship and enabled a dose reduction of each agent at 1.71 and 3.91 folds, respectively, to reach a 90% inhibitory effect when compared to single-agent treatments. Synergistic antitumor activity was further verified in a 3D spheroid culture which revealed, in contrast to single-agent treatment, the combination markedly decreased spheroid volume over time. Together, the combination therapy between Mcl-1 silencing and Dox exhibits a synergistic effect that may be exploited for novel breast cancer treatment.

Albizia myriophylla Benth (Leguminosae) is a medicinal plant widely used in Thailand and other Asian countries as a folk medicine remedy for many ailments. The objective of this study is to investigate the chemical compositions, antibacterial activity, and cytotoxicity of A. myriophylla wood. The structure identification of the isolated compounds was established using spectroscopic methods. In vitro antibacterial activity against Streptococcus mutans, Staphylococcus aureus, and Bacillus cereus and the cytotoxicity against KB cells of extracts and compounds from A. myriophylla were performed using broth microdilution and resazurin microplate assays, respectively. The lupinifolin content in A. myriophylla extracts was quantified by high-performance liquid chromatography. A rare flavan-3,4-diol (1) together with eight known compounds (2-9) were isolated from the wood of A. myriophylla. Compounds 4-9 exhibited anti-S. mutans activity, of which lupinifolin (5) was the most potent with an MIC value of 0.98 µg/mL, followed by its dihydroxy derivative 4 with an MIC value of 62.5 µg/mL. Compounds 4 and 5 also displayed marked antibacterial activity against B. cereus and S. aureus (MIC value 15.63-125 µg/mL) and showed strong cytotoxic activity against KB cells (IC50 value 4.95-12.55 µg/mL). The lupinifolin contents in ethanol extracts from two different collections of this plant originating from central and southern Thailand were 93.85 and 0.04 mg/g, respectively. This is the first report of compounds 1-4 from A. myriophylla. Compounds 4 and 5 showed potent antibacterial and cytotoxic activities compared with other isolates. The anti-S. mutans activity of A. myriophylla extracts seems to be related to the lupinifolin content.