Table 2 List of phytoextracts used in combination with antibiotics against B. anthracis and superbug bacteria for synergistic activity

Stephania tetrandra

Baicalin

β-lactam antibiotics

Ciprofloxacin, Tetracycline

Reduction of β-lactamases in MRSA

Inactivation of NorA, TetK efflux pumps expressed in S. aureus

[1, 207]

Alkaloids, BisbenzylIsoquinoline, Demethyltetrandrine, Tetrandrine

Azithromycin, Ampicillin, Levofloxacin, Cefazolin

Reduces the MIC of MRSA

[282]

Erythrina variegata

Eryzerin-C/Erybraedin-A, Sophoraflavanone-G

Fosfomycin, Levofloxacin, Vancomycin, Gentamicin, Minocycline, Methicillin, Cefzonam

Inactivation of NorA efflux pumps expressed in MRSA and VRE

[226, 283]

Cranberry

Carvacrol

Erythromycin

Reduces MIC of Erythromycin-resistant Group A Streptococci

[284]

–

Tetracycline

Reduces the MIC of S. aureus

[207]

–

Conessine

Cefotaxime, Levofloxacin

Inactivation of MexAB‑OprM efflux pumps expressed in P. aeruginosa

[305]

Artemisia annua

Artemisinins

Penicillin G, Cefazolin, Ampicillin, Cefoperazone, Cefuroxime

Inactivation of AcrAB‑TolC efflux pumps expressed in E.coli

[229]

Curcuma longa Linn

Curcumin

Oxacillin, Norfloxacin

Reduces the MIC of MRSA

[264, 285]

Cipofloxacin, Ampicillin

Gentamicin, Cefepime, Amikacin, Ampicillin, Ceftriaxone,

Meropenem, Imipenem

Prevents or reduces biofilm formation in Gram-positive bacteria

[286]

Ampicillin,

Ciprofloxacin,

Tetracycline, Vancomycin,

Erythromycin,

Gentamicin, Amikacin, Clindamycin,

Fusidic acid, Penicillin

Reduces the MIC of MRSA and MSSA

[287]

Plymyxin B, E

Inactivation of multi-drug resistant EtBr and EmrAB efflux pumps expressed in A. baumannii

[222, 223, 224]

Hedychium coronarium

Coronarin D

Tetracycline, Gentamicin, Rifampicin

Reduces the MIC of B. cereus

[191]

Arctostaphylosuva-ursi

Corilagin

Oxacillin, Cefmetazole

Reduces the fabrication of PBP2a in MRSA

[193]

Jatropha elliptica

2,6-Dimethyl-4-phenyl-pyridine-3,5-dicarboxylic acid diethyl ester

Erythromycin

Inactivation of NorA efflux pumps expressed in S. aureus

[227]

Camellia sinensis (Green tea)

Epigallocatechin gallate

Ampicillin or Sulbactam

Reduction of β-lactamases in MRSA

[202]

Sulfamylon (mafenide acetate)

Reduces MIC of A. baumannii (Clinical isolate)

[164]

Penicillin

Reduction of penicillinase in S. aureus

[288]

Tetracycline

Inactivation of TetK efflux pumps expressed in S. aureus

[215, 217]

Cytisus striatus

Isoflavonoids

Erythromycin, Ciprofloxacin

Inactivation of NorA efflux pumps expressed in MRSA

[228]

–

Cathinone

Ciprofloxacin

Inactivation of acrAB‑TolC efflux pumps expressed in S. typhimurium

[230]

–

Theobromine

Ciprofloxacin, Tetracycline

Inactivation of acrAB‑TolC efflux pumps expressed in S. typhimurium and K. pneumoniae

–

Myricetin

Cefoxitin

Inactivation of NorA efflux pumps expressed in MRSA

[289]

Cefoxitin, Amoxicillin-clavulanate, Ampicillin-sulbactam

Inactivation of NorA efflux pumps in ESBL producing K. pneumoniae and MSSA

[290]

–

Rugosin B

Beta Lactam

Reduction of β-lactamases in MRSA

[1]

–

Totatrol

Methicillin

Reduces the synthesis of PBP2a in MRSA and MSSA

[1, 291]

Glycosmis

5-O-Methylglovanon

Ampicillin

Reduction of β-lactamases in S. epidermidis and S. aureus

[203]

Punica granatum (Pomegranate)

–

Gentamicin, Chloramphenicol, Tetracycline, Ampicillin, Oxacillin

Inactivation of NorA efflux pumps expressed in MRSA

[31]

Herissantia tiubae

Tiliroside

Lomefloxacin, Norfloxacin

Cipofloxacin

Inactivation of NorA multi-drug resistant efflux pumps expressed in S. aureus

[221]

Piper nigrum

Piperine

Ofloxacin

[1]

Green tea

Epicatechin gallate

Oxacillin or Norfloxacin

Inactivation of multi-drug resistant efflux pumps expressed in S. aureus and MRSA

[1, 280, 293]

Ipomoea murucoides

Murucoidin

Norfloxacin

Reduces MIC of MRSA

[294]

Rosmarinus officinalis

Carnosic acid,

Erythromycin

Inactivation of NorA, MsrA efflux pumps expressed in S. aureus

[165]

–

Carnosol

Erythromycin, Tetracycline

Inactivation of NorA, MrsA, TetK efflux pumps expressed in S. aureus

[195]

–

Pinoresinol, Tiliroside, Momorcharaside B, Magnatriol B

β-Lactam antibiotics

Reduces the synthesis of PBP2a and PBP4 in MRSA

MIC reduction and inactivation of CmeABC efflux pumps expressed in C. jejuni

[195]

–

p-Coumaric acid, Caffeic acid, Vanillic acid, Sinapic acid, Gallic acid, Taxifolin

Cipofloxacin, Erythromycin

[231]

Persea lingue

Kaempferol-3-O-α-L-(2,4-bis-E-pcoumaroyl) rhamnoside

Cipofloxacin

Reduces MIC of S. aureus

[214]

Norfloxacin

Inactivation of NorA efflux pumps expressed in S. aureus

–

Reserpine

Moxifloxacin, Sparfloxacin

Ciprofloxacin

Inactivation of NorA efflux pumps expressed in S. aureus

[218]

–

Reserpine

Norfloxacin, Tetracycline, Ciprofloxacin

Inactivation of TetK, NorA, Bmr, MepA efflux pumps expressed in S. aureus, S. pneumonia, B. subtilis

[219, 220]

–

Tannic acid

Tetracycline, Norfloxacin

Inactivation of NorA, TetK efflux pumps expressed in S. aureus

[257]

Berberis fremontii

5'-methoxyhydnocarpin-D, Pheophorbide A

Amikicine, Ampicillin, Tetracycline

Inactivation of NorA multi-drug efflux pumps expressed in S. aureus

[36, 187, 292]

–

Theaflavin

Ampicillin

Reduces MIC of S. maltophilia

[181]

–

Tellimagrandin I

β-Lactam antibiotics

MIC reduction of MRSA

[1, 189, 194]

Wrightia tinctoria

Indoline, indirubin

Ciprofloxacin

Inactivation of NorA efflux pumps expressed in S. aureus

[212, 295]

Alstonia scholaris

–

Cephazolin

MIC reduction of A. baumannii ATCC 19,606

[165, 166]

Adenium obesum

–

Rifampicin

Cerbera odollam

–

Cephazolin

Cerbera manghus

–

Meropenem, Gentamicin,

Nerium oleander

–

Erythromycin

Holarrhena antidysenterica

–

Cephazolin

Plumeria obtusa

–

Cephazolin, Rifampicin,

Wrightia pubescens

–

Streptomycin

Thevetia peruviana

–

Cephazolin, Rifampicin, Fusidic acid

MIC reduction of A. baumannii ATCC 19,606

and P. chlororaphis

[166]

Jatropha curcas

–

Ciprofloxacin, Cefotaxime, Rifampicin, Moxifloxacin, Ofloxacin

MIC reduction of E. coli, P. monteilii, P. aeruginosa, MRSA, E. faecalis, MDR A. baumannii

[180]

–

Catechol, Cinnamic acid, Ellagic acid, Ferulic acid, Gallic acid, Syringic acid, Tannic acid

Novobiocin

MIC reduction of A. baumannii JVC1053

[296]

Ellagic acid, Tannic acid

Novobiocin, Coumermycin, Chlorobiocin, Rifampicin and Fusidic acid

Disruption of efflux pumps present in A. baumannii JVC1053

[225]

Levisticum officinale

–

Cipofloxacin

MIC reduction of A. baumannii NCTC 13,305

[171]

Peganum harmala L,

Cassis italic Mill,

Carthamus tinctorius

–

Ampicillin, Cefotaxime, Vancomycin, Chloramphenicol, Tetracyclines,

Increased inhibition zone diameter of antibiotic against A. baumannii (Clinical isolate)

[172, 173]

Terminalia chebula

–

Cefotaxime

Increased inhibition zone diameter of antibiotic against A. baumannii (Clinical isolate)

[167]

–

Berberine

Ciprofloxacin, Imipenem

MIC reduction of A. baumannii (Clinical isolate)

[88, 297]

Vancomycin

MIC reduction and biofilm disruption of C. difficile

[306]

Punica granatum,

Holarrhena antidysenterica,

Terminalia bellirica,

Quisqualis indica,

Terminalia sp.,

Terminalia chebula

–

Novobiocin

MIC reduction of A. baumannii ATCC 19,606

[168]

Eucalyptus camaldulensis

–

Ciprofloxacin

Polymyxin B, Gentamicin,

MIC reduction of A. baumannii ATCC 19,606, A. baumannii ATCC BAA747, A. baumannii NCTC 13,420

[298]

Allium sativum (Garlic)

Allicin

Cefazolin, Oxacillin

MIC reduction of S. aureus and S. epidermidis

[158]

–

Rosmarinic acid

–

Vancomycin, Amoxicillin, Ofloxacin

MIC reduction of S. aureus ATCC 25,923 and MRSA (Clinical isolate)

[177]

Thymbra spicata L

–

Ampicillin, Amikacin Cefotaxime, Ciprofloxacin

MIC reduction of K. pneumoniae and S. aureus

[307]

Zingiber cassumunar

–

Trimethoprim-sulfamethoxazole, Amoxicillin, Amoxicillin-clavulanic acid, Piperacillin-tazobactam, Ceftazidime, cefepime, Ceftriaxone, Imipenem, Cefotaxime, Meropenem, Ertapenem, Tetracygentamicin, Amikacin,

Gentamicin, Amikacin, Doxycycline, Ciprofloxacin, Levofloxacin, Tetracycline

Increased inhibition zone diameter of antibiotic against XDR A. baumannii

[179]

Holarrhena antidysenterica

Conessine

Novobiocin, Rifampicin

Inactivation of AdeIJK multi-drug efflux pumps expressed in XDR A. baumannii

[207]

Senna italica Mill

–

Tetracyclines, Vancomycin, Ampicillin, Chloramphenicol

Increased inhibition zone diameter of antibiotic against A. baumannii (Clinical isolate)

[173]

Capsicum (chili peppers)

Capsaicin

Ciprofloxacin

Inactivation of NorA efflux pumps expressed in S. aureus

[213]

Pithecellobium clypearia

Gallic acid

Methyl gallate

Ethyl gallate

Pyrogallol

Myricetin-3-O-α-L-rhamnopyranoside

Quercetin-3-O-α-L-rhamnopyranoside

5,3',4',5'-tetrahydroxy-flavan-7-gallate

Epigallocatechin gallate

Imipenem, Cefoperazone, Ceftazidime, Levofloxacin, Amikacin, Tetracycline, Polymyxin B sulfate

MIC reduction of A. baumannii

[175]

Oleanolic acid

Kanamycin, Gentamicin

MIC reduction A. baumannii ATCC 17,978

[178]

Vaccinium macrocarpon Aiton (Cranberry juice extract)

Ferula communis

Plumbago zeylanica

Proanthocyanidin

Levofloxacin

[196]

Tetracycline

Reduces the synthesis of PBP2a in H. pylori Inactivation of AcrAB–TolC multi-drug efflux pumps expressed in E. coli

[308]

Totarol and Ferulenol

Plumbagin

Isoniazid

Inactivation of NorA efflux pumps expressed in M. chelonei, M. smegmatis,

M. intracellulare and M. xenopei

[308]

–

Oleanolic acid

Rifampicin, Isoniazid, Ethambutol

MIC reduction of M. tuberculosis H37Rv (ATCC 27,294) and M. tuberculosis (Clinical isolate)

[309]

Galenia africana L

(E)-3,2′,4′-Trihydroxy-3′-methoxychalcone

(2S)-5,7,2′-Trihydroxyflavonone

Isoniazid

MIC reduction of M. tuberculosis H37Rv

[310]

Euclea natalensis A.DC

7-Methyljuglone

Isoniazid, Rifampicin

MIC reduction of M. tuberculosis H37Rv

[311]

Notopterygium incisum

Isoimperatorin

Rifampicin

MIC reduction of M. tuberculosis H37Rv (ATCC 27,294) and M. tuberculosis (Clinical isolate)

[312]

Piper nigrum L

Piperine

Rifampicin

Inactivation of Rv1258c efflux pumps expressed in M. tuberculosis H37Rv (ATCC 27,294), Rifampicin-resistant M. tuberculosis and MDR M. tuberculosis (Clinical isolate)

[233]

Knowltonia vesicatoria

–

Isoniazid

MIC reduction of M. tuberculosis H37Rv

[313]

Rehum palmatum,

Glycyrrhiza glabra,

Cassia angustifolia, Matricaria chamomilla,

Chichorium intybus

Alkanna tinctoria,

Commiphora molmol,

Curcuma aromatica,

Ferula assa-foetida,

Calligonum comosum,

Rhamnus frangula

Cranberry juice

Ceftasidine, Gentamycin, Tobramycin, Spictinomycin, Cefoperazone

MIC reduction of A. xylosoxidans and S. aureus

[314]

Nalidixic acid, Imipenem, Cefuroxime, Azithro-mycin, Colistin sulphate

Increased inhibition zone diameter of antibiotic against E. coli, P. mirabilis, P. vulgaris, S. typhimurium and S. sonnei

[315]

Vancomycin, Tigecycline

Increased inhibition zone diameter of antibiotic against E. faecalis, E. cloacae and S. aureus, E. faecium

[316]

Cocos nucifera

Ampicillin, Amoxicillin, Chloramphenicol, Penicillin G, Tetracycline, Ciprofloxacin

MIC reduction of E. coli, S. faecalis, L. ivanovii, V. vulnificus and V. fluvialis

[317]

Picralima nitida,

Cassia arereh,

Cylicodiscus gabunensis,

Trichilia emetica

-

Gentamicin, Erythromycin, Kanamycin

MIC reduction of V. cholerae

[183]

Allium sativum L. (Garlic)

Tetracycline, Penicillin, Rifampicin

Cell wall trauma and disruption of cell wall synthesis in B. anthracis

[49]

Peganum harmala L

Cinnamic acid, Ferulic acid,

p-Coumaric acid

Novobiocin, Carbenicillin

Increased inhibition zone diameter of antibiotic against B. anthracis (Clinical isolate)

[182]

Amikacin

Cell membrane trauma and disruption of cell membrane synthesis S. aureus

[196]

Punica granatum

Vangueria madagascariensis

–

Ciprofloxacin

MIC reduction of K. pneumoniae

[242]

Chloramphenicol, Ciprofloxacin

MIC reduction of Acinetobacter spp.

[243]

Berberidaceae spp.

Berberine + 

Azithromycin

The MIC of berberine + azithromycin combination against MRSA was lowered by 50%-96.9% compared to the individual MICs of the two agents

[299]

8‑acetonyl‑dihydroberbine

Levofloxacin

The ability to permeate the cell membrane of MRSA of 8‑acetonyl‑dihydroberbineis possibly superior than that of berberine

Stephania tetrandra

Tetrandrine

Cefazolin

The MIC of tetrandrine + cefazolin combination against MRSA was lower by 75%–94% compared to the individual MICs of the two agents

[283]

Demethyltetrandrine

Cefazolin

The MIC of demethyltetrandrine + cefazolin combination against MRSA was lower by 50%–94% compared to the individual MICs of the two agents

Thymus broussonetii

Borneol/Carvacrol

Pristinamycin

The reduction of cellular PH level caused bacterial cell membrane disruption in V. cholerae, K. pneumoniae, P. aeruginosa

[300]

Thymus maroccanus

Thymol/carvacrol

Ciprofloxacin

MIC reduction of antibiotic against V. cholerae, K. pneumoniae, P. aeruginosa

[300]

Zataria multiflora

Thymol/carvacrol

Vancomycin

The MICs of thymol/carvacrol + vancomycin was lowered from 1 μg/mL to 0.125 μg/mL against S. aureus when used in combination

[301]

Curcuma longa Linn

Curcumin

Polymyxin B

The MIC of curcumin + polymyxin B combination against both clinical and non-clinical isolates of MRSA and A. baumannii was reduced by 3–tenfold compared to the individual MICs of the two agents

[222,223,224]

Horseradish root

Furanone C-30 + horseradish juice

Curcumin

Tobramycin

Significantly reduced in vivo biofilm production in P. aeruginosa due to increased sensitivity to the antibiotic tested via anti-quorum sensing activity of horseradish juice and curcumin

[238]

Oliveria decumbens

Tetracycline, Oxacillin, Doxycycline

Increased inhibition zone diameter of antibiotic against B. melitensis

[184]

Curcumin

Gentamicin

Azithromycin

In vitro anti-biofilm activity mediated by anti-quorum sensing synergism with the selected antibiotics against P. aeruginosa. Plant-antibiotic combinations induced the reduction of autoinducer molecules and down regulation of virulent genes associated with quorum sensing receptors in P. aeruginosa

[239, 240]

Baicalin + hamamelitannin, cinnamaldeyde

Vancomycin

Clindamycin

Tobramycin

Inhibition of biofilm formation in B. cenocepacia, S. aureus and E. coli in in vivo and in vitro assays and increased sensitivity to the antibiotics tested via quorum quenching ability of the isolated phytochemicals

[241]

-

Salicylate

Trimethoprim, Ciprofloxacin, chloramphenicol

Inactivation of ceoR efflux-pumps expressed in B. cenocepacia

[237, 318]