Table 3.

List of some bioactive phytochemicals & their role in combination

Sl no	Combination of active molecules	Observed effect	Mechanism	Ref
1	Curcumin with Amphotericin B	Antifungal & antibacterial action	A synergistically improve action was observed. In this case, the enzyme inhibitory effect of curcumin mainly reported being responsible for enhanced action	[13]
2	Garlic oil and allyl alcohol derived from garlic	Potent antifungal and anti-yeast effect	An additive action was observed. Garlic oil was reported to have cell damage capacity which facilitates the action of allyl alcohol, to show potential killing effect by affecting cytosolic components	[14]
3	Garlic extract with ciprofloxacin	Antibacterial action	The presence of garlic extract improves the inhibitory action of ciprofloxacin	[37]
4	Rifampicin with nalidixic acid	Anti-microbial action	The combination showed enhanced antimicrobial action may be due to synergistic action. Path of mechanism not reported	[15]
5	Fluconazole with cardamom oil & boswellia oil	Antifungal activity	Both the combination shows remarkable improved antifungal action may be due to synergism	[16]
6	Curcumin with fluconazole	Antifungal action against fluconazole-resistant pathogens	The curcumin modulates MDR by inhibiting the transport of fluorescent substrates that are actively effluxes from cells. It improves the sensitivity of fluconazole and, at the same time, practically abolishing cellular growth	[17]
7	Allicin with ketoconazole	Antifungal activity	The combination demonstrates potential antifungal activity due to synergism	[18]
8	Thymol with itraconazole (ITR) & fluconazole (FLU)	Potent antifungal action against resistant strain	Thymol enhances the action probably by disruption of the cell wall/membrane integrity mitogen-activated protein kinase (MAPK) system when used in combination with ITR. It probably creates lesions in the plasma membrane and disruption of ergosterol biosynthesis when used with FLU	[19]
9	Benzoic acid and its derivatives with fluconazole and itraconazole	Enhance antifungal action against resistant strain	Most effectively enhance the antifungal action of azole derivatives utilizing targeting of an oxidative stress response system	[19]
10	Caspofung in with ferulic acid	Antifungal action	The combination shows antifungal action due to synergism	[20]
11	Sulfamethoxazole with myricetin	Synergistic antimicrobial action	The potency of combination increases due to synergism. Myricetin act by DNA binding and induce enzymatic DNA breakage	[21]
12	Tetracycline with epigallocatechin gallate	Synergistic antimicrobial action	Enhances the activity tetracycline against resistant staphylococcal by impairment of tetracycline efflux pump activity and increased intracellular retention of the drug	[22]
13	Sulfamethoxazole with proto catechuic acid, ellagic acid, and gallic acid	Synergistic antibacterial and antifungal action	Improve activity may be due to DNA gyrase and topoisomerase IV enzymes	[21]
14	Sulfadiazine with proto catechuic acid and quercetin	Wide range of antimicrobial action	Reported to have synergism, however, exact mechanisms are unknown	[23]
15	Kaempferol with norfloxacin and ciprofloxacin	Potent antibacterial action	Combinations show synergism and reported possible mechanism involved may be DNA gyrase and DNA topoisomerase IV	[24]
16	Ceftazidime with quercetin analogs	Potent antimicrobial action	A possible reported mechanism states that cell wall damage due to leakage of potassium. Both the compound act at the same target either at different sites	[24]
17	Allium oils with ketoconazole	Fungi static activity	Reported to have synergism. The molecular mechanism was not reported	[18]
18	Berberine with 5’-methoxyhydnocarpin	Potent antimicrobial action	5’-methoxyhydnocarpin (1 mg/mL) inhibited the berberine effluxing multidrug pump and thus increased berberine bioavailability. When combined with subinhibitory amounts of berberine, 5’-methoxyhydnocarpin caused complete inhibition of growth at a concentration of 1 mg/mL	[4]
19	Curcumin with 5-fluorouracil	Anticancer activity	Enhance the capacity of 5-fluorouracil due to synergism. Molecular path not reported	[35]
20	Quercetin with doxorubicin	Anticancer activity	Quercetin combined with cisplatin, exhibited a proapoptotic effect toward human laryngeal carcinoma cells	[25]
21	Resveratrol with doxorubicin	Anticancer activity	Resveratrol facilitates doxorubicin uptake by the cells, probably by downregulation of the expression of mrp-1 (mrp-1 belongs to ATP-binding cassette transporter family, involved in multidrug resistance). It acts as an energy-dependent efflux pump whose overexpression causes a decrease in doxorubicin concentration in the cells	[26]
22	Silibinin with aminoglycosides	Antibacterial action	Improve the action efficacy of aminoglycosides through a significant inhibitory effect on DNA topoisomerase activity due to the formation of complexes that alter enzyme binding	[27]
23	Kaurenoic acid derivatives with fluconazole	Enhance antifungal action against the fluconazole-resistant strain	Kaurenoic acid derivatives enhance the capacity of fluconazole probably due to inhibition of topoisomerase I	[28]
24	Glabridin combination with fluconazole	Effectively improve antifungal activity (fungicidal) of fluconazole	Glabridin facilities membrane permeability & damage cell wall, hence increase the performance of fluconazole	[29]
25	Lactoferrin with fluconazole & itraconazole	Synergistic antifungal activity	Lactoferrin shows synergistic activity in combination with azole derivatives. A possible mechanism may be by promotion or suppression of ergosterol synthesis in the candida cell membrane. Again the iron-chelating function of lactoferrin reported contributing in the synergism	[30]
26	Nisin with thymol	Synergistic antimicrobial activity	Destabilization of bacterial membrane structure resulting in an increased permeability for nisin which leads to bacterial cell lysis	[31]
27	Carnosic acid with tetracycline	Antimicrobial activity	Possible mechanism reported inhibiting the MDR pumps	[3]