Antibacterial activity of medicinal plants against ESKAPE: An update.

Antibiotic resistance has emerged as a threat to global health, food security, and development today. Antibiotic resistance can occur naturally but mainly due to misuse or overuse of antibiotics, which results in recalcitrant infections and Antimicrobial Resistance (AMR) among bacterial pathogens. These mainly include the MDR strains (multi-drug resistant) of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). These bacterial pathogens have the potential to "escape" antibiotics and other traditional therapies. These bacterial pathogens are responsible for the major cases of Hospital-Acquired Infections (HAI) globally. ESKAPE Pathogens have been placed in the list of 12 bacteria by World Health Organisation (WHO), against which development of new antibiotics is vital. It not only results in prolonged hospital stays but also higher medical costs and higher mortality. Therefore, new antimicrobials need to be developed to battle the rapidly evolving pathogens. Plants are known to synthesize an array of secondary metabolites referred as phytochemicals that have disease prevention properties. Potential efficacy and minimum to no side effects are the key advantages of plant-derived products, making them suitable choices for medical treatments. Hence, this review attempts to highlight and discuss the application of plant-derived compounds and extracts against ESKAPE Pathogens.

Introduction

Many new antibiotics have been produced in the last four decades by pharmacological industries, and resistance by microorganisms to these drugs have been accelerated due to impetuous use of antibiotics. A report submitted to the United Nations in 2019, expects that infections caused by antibiotic resistant bacteria would cause 10 million deaths per annum and an economic crisis just like the 2008–2009 global financial collapse by 2050 [1]. Antimicrobial Resistance (AMR) can be conferred in bacteria via genetic mutation and Horizontal Gene Transfer (HGT) through chromosomes, plasmids, transposons and other mobile genetic elements [2]. AMR is a natural prevalence that is connected to a rise in "mortality, morbidity and economic burden" of nations worldwide [3]. Till date, there have been no evidences for effective antimicrobial compounds against the AMR bacteria caused infections [4, 5]. Thus, there is an immediate need for novel treatment methods targeting the issues caused by AMR.

Global priority pathogen list (PPL) was released by the World Health Organization (WHO) in 2016 to guide the researcher in discovery, and development of new antibiotics [6]. In this sequence the five-year NAP (National Action Plan) for the control of AMR (2017–2021) that was developed by the Indian Ministry of Health and Family Welfare in April 2017, was presented at the 70th World Health Assembly (WHA) held at Geneva in May 2017. It geared towards increasing awareness, surveillance and investment in research to combat the spread of AMR. However, there are many hurdles to overcome such as lack of funding, strict implementation and ethical commercial practices [7].

[8]. .

The European Center for Disease Control (ECDC) and the Center for Disease Control (CDC) in USA gave the subsequent standardized definitions for multidrug resistant (MDR), extensively drug resistant (XDR), and pan drug resistant (PDR) bacteria: multidrug resistance (MDR) is defined as acquired non-susceptibility to a minimum of one agent in three or more antimicrobial categories. Extensively drug resistance (XDR) is defined as non-susceptibility to a minimum of one agent altogether but two or fewer antimicrobial categories (i.e., bacterial isolates remain vulnerable to just one or two antimicrobial categories). The non-susceptibility to all agents in all antimicrobial categories is called Pan Drug Resistance (PDR) [9].

For a long period of time people of India have been using many plant species as traditional medicines for a variety of ailments, including treatment of infectious diseases [10]. Discovery of novel drugs can be accomplished with the use of plants extracts, which is a reservoir of broad-spectrum secondary metabolites [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. Plants have proven themselves to be effective in preventing and treating the toxicity induced by other toxins or drugs. The efficacy of plant extracts and their derivatives in terms of their antimicrobial activities have paved the way for the exploration of new and effective treatments against MDR-ESKAPE. This review targets the use of such diverse traditional medicinal plants, which are capable of being used effectively as anti-ESKAPE drugs.

ESKAPE: a threat to public health

Antimicrobial resistance represents a global threat to human health. AMR is found in both Gram-positive and Gram-negative strains of bacteria. India's AMR rates are alarmingly high when compared to other nations. For instance, the percentage of clinical isolates of MRSA (Methicillin Resistant Staphylococcus aureus) nearly doubled over a period of just 6 years (2008–2014) from 29% to 47%. Other nations reported a decline in the percentage of MRSA as a result of extensive antibiotic stewardship and awareness practices [24]. The Carbapenem resistant A. baumannii, P. aeruginosa, K. pneumoniae, E. faecium, Methicillin resistant, vancomycin intermediate/resistant S. aureus and other members of Enterobacteriaceae are [25] known as “superbugs” or ESKAPE. The above mentioned pathogens are responsible for lethal infections amongst critically ill and immunocompromised individuals as a result of lack of treatment [26]. Thus the consequences of ESKAPE could be devastating.

Enterococcus faecium (E. faecium)

is a Gram-positive spherical (cocci) bacterium that occurs in pairs or chains, commonly involved in nosocomial infections amongst immunocompromised patients. β-lactam antibiotics such as penicillin and other last resort antibiotics have no effect on E. faecium. [27]. Resistance to Vancomycin, in particular, has led to a significant increase in Vancomycin resistant Enterococci (VRE) strains [27]. A gene of VRE encodes for a putative Enterococcal Surface Protein that aids in the formation of thicker biofilms [28]. Infections caused by it include urinary tract infections (UTI), bacteremia, intra-abdominal infections, and endocarditis. Enterococci are now the third most common nosocomial pathogen that caused 14% of hospital-acquired infections in the United States between 2011 and 2014, compared to 11% in 2007. Aside from nosocomial infections, enterococci are responsible for 5–20% of community-acquired endocarditis [29].

Staphylococcus aureus (S. aureus)

is a Gram-positive spherical (coccus) bacteria that's commonly found in human skin microbiota and is typically harmful only in immunocompromised individuals. Being a part of normal microflora of skin, it usually causes infections when it invades the regions that it typically does not inhabit, such as bruises and wounds. S. aureus is capable of causing infections on medical implants and forming biofilms that poses a challenge in antibiotics mediated treatment. Moreover, approximately 25% of S. aureus strains secrete the TSST-1 exotoxin which is responsible for causing toxic shock syndrome. Methicillin-resistant S. aureus (MRSA), a special strain of S. aureus, is known to have evolved resistance against β-lactam antibiotics [27]. They confer resistance to β-lactam antibiotics by the expression of mecA that encodes a low penicillin binding affinity protein (PBP 2a) [30]. They are associated with an increasing number of health care related infections, particularly seen in infective endocarditis and prosthetic device infections. Also, strains with particular virulence factors and resistance to β-lactam antibiotics are some of the major causes of community-associated skin and soft tissue infections [31]. Certain S. aureus strains have been identified as resistant to Vancomycin-intermediate owing to the overuse of the drug for the treatment of S. aureus [32].

Klebsiella pneumoniae (K. pneumoniae)

is a Gram-negative rod-shaped (bacillus). According to Shiri et al., about one-third of all Gram negative infections such as UTI, Septicemia, Surgical Wound Infections, Cystitis, Pneumonia and endocarditis can be attributed to this organism. It is also known to cause necrotizing pneumonia, pyogenic liver abscesses and endogenous endophthalmitis. K. pneumoniae infections account for its high mortality rates, extended hospitalization, coupled with expensive treatments. A significant rise in the occurrence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) pathogens of the Enterobacteriaceae group is posing a global economic threat nowadays. Certain strains have been classified as carbapenem-resistant K. pneumoniae (CRKP), because of the development of β-lactamases, which makes them resistant to commonly used antibiotics, such as carbapenems. There are only a few antibiotics in development which will treat infection [27, 33, 34].

Acinetobacter baumannii (A. baumannii)

A. baumannii is a Gram-negative, strictly aerobic, non-fermenting, non-fastidious, catalase-positive, oxidase-negative coccobacillus or pleomorphic bacterium that is responsible for almost 2 per cent of all nosocomial infections in the US and Europe and twice as high in Asia and the Middle East. 45% of all isolates of this deadly, opportunistic pathogen around the world have been reported as Multidrug Resistant (MDR). The most usual types of infections caused by this bacterium are Central line- associated bloodstream infections and ventilator-associated pneumonia. The ability to resist desiccation, form biofilms and presence of fundamental virulence factors, such as surface adhesins, glycoconjugates and secretion systems help A. baumannii to thrive in this environment [35].

Pseudomonas aeruginosa (P. aeruginosa)

is a Gram-negative, gamma-proteobacterium possessing a lowly permeable outer membrane and multiple transport systems that provide it innate resistance to many antibiotics. It also employs a variety of mechanisms such as alterations in porin channels, efflux pumps, target modifications, and β-lactamases that allow it to develop resistance to antimicrobial agents [36]. Cystic fibrosis (CF) patients are at a particularly high risk of acquiring this infection because of its ability to form biofilms and persister cells in the lungs [37]. Point mutations on DNA gyrase/Topoisomerase IV provide immense resistance against Fluoroquinolones to P. aeruginosa [38].

Enterobacter spp.

are Gram-negative, facultatively anaerobic, rod-shaped bacteria that are members of the Enterobacteriaceae family. Immunocompromised patients such as those on mechanical ventilation or implanted with IMD are most susceptible to urinary or respiratory tract infections by this pathogen. E. cloacae is the most commonly found species in patients causing 4%–5% of all nosocomial bacteraemia, pneumonia and urinary tract infections [39]. They show broad resistance to antimicrobials by plasmid encoded ESBLs, carbapenems [4].

Plant derived compounds and extracts against ESKAPE

Conventional medicinal practices utilize plants against various infections for over thousands of years now [40, 41, 42, 43]. 80% of the population in the developing nations are dependent upon the easily accessible traditional medications to fulfil their primary medical needs, [44, 45]. Indeed, plants are known to synthesize a wide array of compounds known as secondary metabolites or phytochemicals such as quinones, tannins, terpenoids, alkaloids, flavonoids, and polyphenols which have disease prevention properties and aid them in their self-defense and communication with other organisms in their environment [46]. Plant extracts as medicines are inevitable substitutions for antibiotics prescribed by physicians [47] Plant derived compounds and extracts are commonly used in self-medication due to its easy availability, competence and nil side effects [47].

Table 1 shows a total of 100 plants that were reported to show significant antimicrobial activity against ESKAPE pathogens during the period of 2006–2020. These plants were reported from 12 countries from Asia, Africa, Europe, North America and South America. India reported the highest number (35) of plants (Chart 1).

Table 1

Plant-derived compounds and plant extracts reported during 2006–2020 against ESKAPE.

S. No.	Scientific Name		Common Names		Parts used		Traditional uses		Extract prepared in	Anti -microbial activity against	References
1	Cinnamomum glaucescens		Sugandhakokila		Leaves		Skin and throat infection		Acetone	MRSA	Panda et al., 2020 [48]
2	Smilax zeylanica		Kumarika		Leaves		Ulcers treatment		Acetone	MRSA	Panda et al., 2020 [48]
3	Syzygium praecox		N/A		Leaves		Skin infection		Acetone	MRSA	Panda et al., 2020 [48]
4	Trema orientalis		Charcoal tree		Leaves		Sore throat, boils, wound infections		Acetone	MDR-S	Panda et al., 2020 [48]
5	Bischofia javanica		Java cedar		Leaves		Skin diseases		Acetone	MDR-S	Panda et al., 2020 [48]
6	Elaeocarpus serratus		Ceylon olive		Flower		Acts as a diuretic and cardiovascular stimulant		Water	MDR-S	Panda et al., 2020 [48]
7	Acacia pennata		Climbing acacia		Leaves		Effective against dysentery, diarrhoea and lowers body cholesterol		Ethanol	MRSA	Panda et al., 2020 [48]
8	Holigarna caustica		Long-leaf varnish tree		Fruit		Skin diseases		Ethanol	MRSA	Panda et al., 2020 [48]
9	Murraya paniculata		Orange jessamine		Leaves		Cure to cardiovascular disorders		Ethanol	MRSA	Panda et al., 2020 [48]
10	Pterygota alata		Buddha coconut		Bark		Skin diseases		Ethanol	MDR-S	Panda et al.,2020 [48]
11	Kalanchoe fedtschenkoi		Lavender scallops		Woody stems		Used as an analgesic (Cumberbatch, 2011) [49]		Ethanol	S,A,P	Richwagen et al.,2019 [50]
12	Bridelia micrantha		Coastal golden leaf		Stem bark		Used in Cameroon to treat amoebic dysentery, cough diarrhoea, gastric ulcer, eye diseases, infertility and tapeworms. Has antibacterial, hepatoprotective, antioxidant, antitumor and antiviral activities		Methanol	S, K, P, MRSA, Ea	Ngane et al., 2019 [51]
13	Prunus cerasifera		Cherry plum		Fruit		Astringent, antioxidant, sudorific, antipyretic, axative and diuretic properties		Methanol	K,S,P	Pallah et al., 2019 [52]
14	Ribes nidigrolaria		Jostaberry		Fruit		Anti-aging, cataracts, cardiovascular disease, immunity.		Methanol	P,S	Pallah et al., 2019 [52]
15	Prunus avium		Sweet Cherry		Fruit		Cancer, osteoarthritis and cardiovascular disease		Methanol	K,S,P	Pallah et al., 2019 [52]
16	Prunus subg. Prunus		Plum		Fruit		Antioxidant, anti-inflammatory, and memory-boosting properties		Methanol	K,S,P	Pallah, et al., 2019 [52]
17	Ribes rubrum		Red Currant		Fruit		To treat scurvy, relieve constipation, digestive and urination issues, laxative		Methanol	K,S,P	Pallah et al., 2019 [52]
18	Adiantum capillus-veneris		Maiden hair fern		Whole plant		Urinary tract infections (UTIs); also used as an astringent, demulcent, antitussive and diuretic(Ishaq et al., 2014) [53]		Ethanol	Ef,S	Khan et al., 2018 [54]
19	Artemisia absinthium		Worm wood		Aerial parts		Pruritus and inflammatory and infectious skin disorders, (Khan and Khatoon, 2008) [55]Drugs against malaria and typhoid (Hayat et al., 2009) [56]		Ethanol	Ef,S	Khan et al., 2018 [54]
20	Martynia annua		Bichoo		Fruit		Wound healing, skin conditions and sore throats (Santram and Singhai, 2011; Dhingra et al.,2013) [57,58]		Ethanol	K,A,Ef,S	Khan et al., 2018 [54]
21	Swertia chirata		Chirayita		Whole plant		Hepatitis, inflammation and digestive diseases. Other indications include chronic fever, malaria, skin disease and bronchial infections (Kumar and Van Staden, 2016) [59].		Ethanol	S	Khan et al., 2018 [54]
22	Zanthoxylum armatum		Timber		Fruit		Cancer and digestive ailments such as cholera and dysentery, dental infections and oral sores (Ahmad et al., 2014;Alam and Saqib, 2017) [60, 61].		Ethanol	Ef,S	Khan et al., 2018 [54]
23	Berberis lycium Royle		Indian Lycium		Root		Bark infusions are traditionally used for oral infections, toothaches and earaches (Abbasi et al., 2010) [62]. Traditionally used to treat diarrhea, cholera and piles (Malik et al., 2017) [63].		Ethanolic and Aqueous	Ef	Khan et al., 2018 [54]
24	Anacardium occidentale		Cashew		leaves		Venereal diseases, stomach issues, skin diseases, stomatitis, bronchitis, psoriasis, toothaches, and gum problems		Ethanol	K, P, S	Shobha et al., 2018 [64]
25	Piper longum		Pipli		Root		Antioxidant potential and anti-inflammatory properties		Aqueous	Ef, A	Chandrasekharan et al., 2018 [65]
26	Cymbopogon citratus		Lemon grass		Leaves		Treatment against hypertension, epilepsy, gastrointestinal, central nervous system disorders		Hexane	P, Ec	Chandrasekharan et al., 2018 [65]
27	Aloe vera		Medicinal aloe		Leaves		Help with skin injuries caused by burning, irritations, cuts, actively repairs damaged skin		Aqueous	S	Chandrasekharan et al., 2018 [65]
28	Cynodon dactylon		Bermuda grass		Leaves		Laxative, coolant, brain and heart tonic		Ethanol	K	Chandrasekharan et al., 2018 [65]
29	Theobroma cacao		Cocoa		SeedsLeaves		Stimulates nervous system, low blood pressure and softens damaged skin. Effective against anemia, diarrhea and bruises		Methanol	KEa	Nayim et al., 2018 [66]
30	Ipomoea batatas		Sweet potato		Leaves		Treatment of diabetes, hypertension, and stomach related issues, arthritis, rheumatoid diseases, meningitis, kidney ailments, and inflammations.		Methanol	Ea	Nayim et al., 2018 [66]
31	Azadirachta indica		Neem tree		Bark		Used to treat teeth-related issues and disorders of the GI tract, malaria fevers, skin diseases, and as insect repellent		Methanol	Ea, K	Nayim et al., 2018 [66]
32	Citrus grandis		Pomelo		Leaves		To treat epilepsy, chorea, Convulsive cough and also in the treatment of hemorrhage disease.		Methanol	K	Nayim et al., 2018 [66]
33	Cucurbita maxima		Winter squash		Beans		Treat intestinal infections and kidney problems and to fight tapeworms		Methanol	K	Nayim et al., 2018 [66]
34	Dacryodes edulis		Bush butter tree		Leaves seeds		Gargle and mouth wash to treat tonsillitis		Methanol	Ea, EcEa, P	Nayim et al., 2018 [66]
35	Hibiscus esculentus		Okra		Leaves		Used in the treatment of nose and throat related infections, urine associated issues and gonorrhoea		Methanol	Ea	Nayim et al., 2018 [66]
36	Phaseolus vulgaris		Common bean		Leaves		Consumed orally for weight loss and obesity. Taken for diabetes as well		Methanol	Ea, P	Nayim et al., 2018 [66]
37	Lantana camara		Lantana		Leaves		Antispasmodic, anti-tumor, anti-inflammatory, anti-malarial,anti-ulcerogenic		Dichloromethane, methanol, petroleumether, chloroform,ethyl acetate, acetone,ethanol and water	MRSA, MDR-A, VRE, P	Subramani et al., 2017 [67]
38	Butea monosperma		Palash		Leaves		Stimulation of diuresis and menstrual flow.		Petroleum ether, acetone, methanol, ethanol and water	MRSA, VRS	Subramani et al., 2017 [67]
39	Terminalia chebula		Myrobalan		Dried seedless ripe fruits		Treats High cholesterol and digestive disorders, dysentery		Cold and hot aqueous and ethanol	MRSA	Subramani et al., 2017 [67]
40	Anthocephalus cadamba and Pterocarpus santalinus		Burflower tree and red sandalwood		Leaves and bark		Treatment of fever, uterine complaints, skin diseases, inflammation. Antipyretic, dysentery, antihyperglycaemic		Ethanol and water	MDR-A species, P	Subramani et al., 2017 [67]
41	Andrographis paniculata		Green chireta		-		Anti-cancer, anti-diabetic, helps overcome high blood pressure, ulcer, lung related issues, skin diseases		Chloroform and chloroform + HCl	MRSA	Subramani et al., 2017 [67]
42	Callistemon rigidus		Stiff bottlebrush		Leaves		Treatment of diarrhea, dysentery, rheumatism, anticough and antibronchitis		Methanol	MRSA	Subramani et al., 2017 [67]
43	Myrtus communis		Myrtle		Leaves		Diabetes, ulcers, hypertension, dysentery, rheumatism, cancer, inflammations and diarrhea		Hydro-alcoholic	P, S	Masoumian and Zandi, 2017 [68]
44	Cinnamomun zeylanicum		Cinnamon		Bark		Antioxidant, anti-inflammatory, anti-diabetic properties		Water	P, S	Masoumian and Zandi, 2017 [68]
45	Mentha sp.		Mint		Leaves		Effective against cold, irritable bowel syndrome, indigestion		Aqueous hydro-alcoholic	PS	Masoumian and Zandi, 2017 [68]
46	Lawsonia inermis		Henna		Leaves		Heals wounds and burns, used for skin infections, hair health		Aqueous	P, S	Masoumian and Zandi, 2017 [68]
47	Aloe vera		Medicinal aloe		Leaves		Burns, acne, oral and digestive problems		Aqueous	P, S	Masoumian and Zandi, 2017 [68]
48	Zingiber officinale		Ginger		Roots		Nausea, vomiting, anti-cancer		Hydro-alcoholic	P, S	Masoumian and Zandi, 2017 [68]
49	Bulbine frutescens		Snake flower		Leaves and bulbs		Skin and wound conditions. (Van Wyk et al., 2009; Diederichs et al., 2009) [69, 70]		Chloroform and methanol	S,P	Ghuman et al.,2016 [71]
50	Aloe ferox		Bitter Aloe		Leaves		Skin conditions (Van Wyk et al., 2009; Diederichs et al., 2009) [69, 70]		Chloroform	S,P,K	Ghuman et al., 2016 [71]
51	Mentha longifolia		Horse mint		Aerial parts		Throat irritation, mouth and sore throat (Al-Bayati, 2009) [72]		Ethanol	VRE	Agarwal et al., 2016 [73]
52	Phyllanthus emblica		Amla		Aerial parts		Antimicrobial, anti-inflammatory, antioxidant, anti pyretic, analgesic, adaptogenic, hepatoprotective (Gulati et al., 1995; Baliga et al.,2012) [74, 75]		Ethanol	MRSA, VRE	Agarwal et al., 2016 [73]
53	Aloe arborescens		Tree Aloe		Leaves		Skin, digestive and respiratory conditions (Hutchings et al., 1996; Crouch et al., 2006; Klos et al., 2009; Van Wyk et al., 2009) [69, 76, 77, 78]		Dichloromethane	S,P	Ghuman et al.,2016 [71]
54	Hypericum aethiopicum		N/A		Leaves		Skin and gastrointestinal issues. (Rood, 1994; Bruneton, 1995; Hutchings et al., 1996; Van Wyk et al., 2009) [69, 76, 79, 80]		Dichloromethane, Chloroform, Methanol.	S,K	Ghuman et al., 2016 [71]
55	Aframomum corrorima		Ethiopian Cardamom		Fruit		Substitute medication for the regional community and scientific research in search for substitute drugs to overcome challenges associated with the rising antimicrobial resistance		_	S	Bacha et al., 2016 [81]
56	Camellia sinensis		GreenTea		Leaves		Anticancer activity, Cardiovascular Diseases (Miura et al., 2000; Smith and Dou, 2001) [30, 82]		Ethanol	MRSA	Agarwal et al., 2016 [73]
57	Mentha longifolia		Horse mint		Aerial parts		Throat irritation, mouth and sore throat (Al-Bayati, 2009) [72]		Ethanol	VRE	Agarwal et al., 2016 [73]
58	Phyllanthus emblica		Amla		Aerial parts		Antimicrobial, anti-inflammatory, antioxidant, anti pyretic, analgesic, adaptogenic, hepatoprotective (Gulati et al., 1995; Baliga et al., 2012) [74, 75]		Ethanol	MRSA, VRE	Agarwal et al., 2016 [73]
59	Oxalis corniculata		Yellow sorrel		Leaves		Digestion, chronic dysentery, diarrhea, headaches, intoxication, fever, inflammations, jaundice, pain, scurvy, anti-helminthic, analgesic, astringent, diuretic		Methanol	K,S	Manandhar et al., 2015 [83]
60	Cinnamomum tamala		Bay leaf		Leaves		Diabetes, Digestion, Cardiovascular Benefits, Cold and Infection, Pain, Anti-cancer, Menstrual Problems		Methanol	S	Manandhar et al., 2015 [83]
61	Ageratina adenophora		Cotton weed		Leaves		Cuts, wounds, boils, antiseptic		Methanol	S	Manandhar et al., 2015 [83]
62	Artemesia vulgaris		Mugwort		Aerial parts		Antiseptic, diarrhea, dysmenorrhea, asthma, antihelminthic, stomach ulcer, anorexia, heartburn, hyperacidity, spasm of digestive organs, epilepsy		Methanol	S	Manandhar et al., 2015 [83]
63	Cynodon dactylon		Bermudagrass, Doob grass		Whole plant		Cuts, wounds, indigestion,genitourinary disorders (Rajbhandari., 2001; Manandhar, 2002; Singh et al., 2012) [84, 85, 86]		Ethanol, Chloroform	MRSA,IRP,ESBL-K	Quinn et al., 2015 [87]
64	Curcuma longa		Turmeric		Rhizomes		Antiseptic, cuts, wounds, as anthelmintic, jaundice, liver disorders (Rajbhandari., 2001; Manandhar, 2002; Singh et al., 2012) [84, 85, 86]		Ethanol and Chloroform	MRSA, Ef	Quinn et al., 2015 [87]
65	Ginkgo biloba		Ginkgo		Leaves		As antiaging, used to treat Alzheimer’s disease, as anticoldness, as antinumbness (Rajbhandari, 2001; Manandhar, 2002) [84, 85]		Ethanol and Chloroform	S,Ef	Quinn et al., 2015 [87]
66	Rauwolfia serpentine		Serpentine (Sarpagandha)		Root		As antidysenteric, as antidote to snakebite, cuts, wounds, and boils (Rajbhandari., 2001; Manandhar, 2002; Singh et al., 2012) [84, 85, 86]		Ethanol and Chloroform	MRSA,S, Ef, IRP,ESBL- K	Quinn et al., 2015 [87]
67	Croton macrostachyus Del.		Rushfoil		Leaves		Veterinary: diarrhea (dysentery), external parasites etc. (Adedapo et al., 2008) [88]		Methanol and Chloroform	S,P	Romha et al., 2015 [89]
68	Calpurnia aurea		Wild laburnum		Leaves		Human: diarrhea, dysentery, and stomach disorder (Wagate et al., 2010) [90]		Methanol and Chloroform	S,P	Romha et al., 2015 [89]
69	W. somnifera L.		winter cherry		Roots		Human: extended flow of menstruation/menometrorrhagia (bark & leaf), gallstone (root & leaf) (Alam et al., 2012) [91]		Methanol and Chloroform	P	Romha et al., 2015 [89]
70	Nicotiana tabacum L.		Tobacco		Leaf		Used to treat infected wounds, hair treatment to prevent baldness, used in case of chills, snake bites		Methanol and chloroform	S, P	Romha et al., 2015 [89]
71	Phyllanthus niruri		Sampa-sampalukan		Leaves, aerial parts		Problems of stomach, genitourinary system, liver, kidney and spleen, and to treat chronic fever (Kamruzzaman and Obydul Hoq, 2016) [92]		Ethanol	MRSA, VRE, S	Demetrio et al., 2015 [93]
72	Psidium guajava		Bayabas		Leaves		Anti-diarrhoeal, to treat gastroenteritis, dysentery, stomach problems (Martha et al., 2008) [94]		Ethanol	MRSA, VRE, S	Demetrio et al., 2015 [93]
73	Piper betle		Ikmo		Leaves		Mouth freshener, effective against parasitic worms, antibacterial, antifungal, antioxidant and anti-inflammatory activities (Fazal et al., 2014) [95]		Ethanol	MRSA, MβL A, MβL P, VRE, ESBL-KP, S, K,P	Demetrio et al., 2015 [93]
74	Ehretia microphylla		Tsaang gubat		Leaves		Antibacterial, antioxidant, anti-allergic as well as anti-snake venom properties (Shukla et al., 2018) [96]		Ethanol	MRSA, MβL A, VRE, S, P	Demetrio et al., 2015 [93]
75	Tabebuia impetiginosa		Tahuari		Whole plant		Treatment of rheumatism and, wounds, bronchitis and diarrhea.		Ethanol	P	Ulloa-Urizar et al., 2015 [97]
76	Maytenus macrocarpa		Chuchuhuasi		Whole plant		Urine related issues, anti-cancerous, syphylis, gasterointestinal problems, diabetes		Ethanol	P	Ulloa-Urizar et al., 2015 [97]
77	Eucalyptus camaldulensis		River red gum		-		Hot water extracts of dried leaves used as analgesic, anti-inflammatory and antipyretic remedies for the symptoms0 of respiratory infections, such as cold, flu, and sinus congestion. (Darwish and Aburjai, 2010) [98].		Ethanol	P	Amenu, 2014 [99]
78	Ficus sycomorus		Sycamore fig		Leaves		Ficus sycomorus have been suspected to possessanti-diarrhoeal activities and sedative and anticonvulsant properties of this plant have also been reported. (Cuaresma et al.,2008) [100]		Methanol and Aqueous	S	Amenu, 2014 [99]
79	Entada abyssinica		Splinter bean		Leaves and roots		Coughs, fever, rheumatic, abdominal pains, and diarrhea, prevent miscarriage,gonorrhea, Bronchite, eyes inflammation,snake bite, sleeping sickness		Methanol	S, K	Tchana et al., 2014 [101]
80	Carica papaya		Papaya		Seeds		Typhoid fever, parasitic diseases, hepatic affections, dyspepsia, colic,gastric ulcer, toothache, analgesic,amebicide, antibacterial, febrifuge,hypotensive, laxative		Ethanol and aqueous	K, P	Tchana et al., 2014 [101]
81	Carapa procera		Carapa		Bark		Wound infections		Ethanol	P	Tchana et al., 2014 [101]
82	Persea americana		Avocado		Stones		Diarrhea, dysentery, toothache, intestinal parasites, hypertension, cancer,menstrual problems, inflammation,wounds		Methanol, ethyl acetate and chloroform	K, P	Tchana et al., 2014 [101]
83	Adansonia digitata		African baobab		Pulps, Fruits, leaves, Pip, Bark		Analgesic, anti-diarrheal, smallpox, rubella, antipyretic, fever, dysenteria, anti-inflammatory, astringent (Tanko et al., 2008; Kaboré et al., 2011) [102,103]		Ethanol and Aqueous Extract	S,P	Djeussi et al., 2013 [104]
84	Aframomum polyanthum		Matunguru		Fruits		-		Methanol	S	Djeussi et al., 2013 [104]
85	Hibiscus sabdarifa		Roselle		Flowers		Diuretic, stomachic, laxative, aphrodisiac, antiseptic, astringent, cholagogue, sedative, hypertension and other cardiac diseases (Olaleye, 2007) [105]		Ethanol, Methanol,Aqueous	S,K,P	Djeussi et al.,2013 [104]
86	K. pinnata		Cathedral bells		Leaves		Healing of Wounds caused by S and P, anti-microbial properties		95% Ethanolic, 60% Methanolic and Aqueous	S,P	Pattewar et al., 2013 [106]
87	Acacia karroo		Sweet thorn		Stem		Mouth ulcers, oral thrush, diarrhea, dysenteries, colic, colds, other Acacia pecies: asthma, bronchitis, cough, phithisis, fever, leprosy, chest and respiratory ailments (Watt and Breyer-Brandwijk, 1962; Johnson, 1999; Van Wyk et al., 2006) [107, 108, 109]		Methanol	ARKP	Nielsen et al., 2012 [110]
88	Curtisia dentate		Assegaai tree		Stem bark		Stomach ailments, diarrhea, blood purifier, afrodisiac, tanning, chewing sticks (Watt and Breyer-Brandwijk, 1962; Van Wyk et al., 2006) [107, 109]		Methanol	MRSA	Nielsen et al., 2012 [110]
89	Erythrophleum lasianthum		Sasswood		Stem and leaves		Headaches, fever, Erythrophleum species: heart problem, dermatitis, wounds, rheumatism, syphilis, gonorrhea, leprosy, tuberculosis, bronchitis, angina, ordeal and hunting poison (Palgrave et al., 1988; Neuwinger, 1996; Johnson, 1999) [108, 111, 112]		Methanol	MRSA	Nielsen et al., 2012 [110]
90	Salvia africana-lutea		Golden sage		Aerial parts		Colds, flu, bronchitis, abdominal and uterine troubles, cough, chest troubles, other Salvia species: night sweat tuberculosis, respiratory and pulmonary ailments (Watt and Breyer-Brandwijk, 1962; Johnson, 1999; Van Wyk et al., 2006) [107, 108, 109]		Methanol	MRSA	Nielsen et al., 2012 [110]
91	Toddalia asiatica		Orange climber		Leaves		Traditionally used to treat malaria and cough; indigestion and influenza and the leaves are used to treat lung diseases and rheumatism.		Ethyl acetate	K, Ea	Karunai Raj et al., 2012 [113]
92	Kalanchoe pinnata		Patharkuchi		Stems and leaves		Diarrhea, dysentery and gastrointestinal disturbances. (Pal et al., 1991) [114]		Ethanol	S,P	Biswas et al., 2011 [115]
93	Acacia nilotica		Gum Arabic Tree		Leaves		Antimicrobial, antihyperglycemic and antiplasmodial properties		Ethanol	K	Khan et al., 2009 [116]
94	Cinnamum zeylanicum		Cinnamon		Barks		Antipyretic activity, antibacterial, antioxidant and antifungal properties		Ethanol	K	Khan et al., 2009 [116]
95	Syzygium aromaticum		Clove		Bud		Antipyretic activity, antibacterial, antifungal, anti-inflammatory and anticarcinogenic effects		Ethanol	K	Khan et al., 2009 [116]
96	Syzygium lineare		Malai naaval		Leaves		Diuretic, stomachic, tonic and astringent (Nadkarni, 1976; Rastogi and Mehrotra, 1990–1994; Narasimhan, 2003) [117, 118, 119]		Hexane and Methanol	S	Duraipandiyan et al., 2006 [120]
97	Acalypha fruticosa		Chinni chedi		Aerial parts		Stomachic, attenuate (Nadkarni, 1976; Rastogi and Mehrotra, 1990–1994; Narasimhan, 2003) [117, 118, 119]		Hexane	P,S	Duraipandiyan et al., 2006 [120]
98	Syzygium cumini		Naval pazham		Seed		Astringent, stomachic, diuretic, tonic and anti-diabetic (Nadkarni, 1976; Rastogi and Mehrotra, 1990–1994; Narasimhan, 2003) [117, 118, 119]		Methanol	S,K	Duraipandiyan et al., 2006 [120]
99	Olax scandens		Kaattu pavalam		Leaves		Febrifuge (Nadkarni, 1976; Rastogi and Mehrotra, 1990–1994; Narasimhan, 2003) [117, 118, 119]		Hexane	K	Duraipandiyan et al., 2006 [120]
100	Peltophorum pterocarpum		Malai porasu		Flower		Applied topically to treat wounds (Nadkarni, 1976; Rastogi and Mehrotra, 1990–1994; Narasimhan, 2003) [117, 118, 119]		Methanol	K	Duraipandiyan et al., 2006 [120]

KEY TO ABBREVIATIONS: Ef = Enterococcus faecium, K = Klebsiella pneumoniae, P = Pseudomonas aeruginosa, S = Staphylococcus aureus A = Acinetobacter baumannii, MRSA = Methicilin resistant Staphylococcus aureus, IRPA = Imipenem resistant Pseudomonas aeruginosa, ESBL-KP = Extended spectrum β lactamase producing Klebsiella pneumoniae, ARKP = Ampicillin resistant Klebsiella pneumoniae, Ec = E. cloacae, MDR-A = Multidrug resistant Acinetobacter baumannii, VRE = Vancomycin resistant E. faecium, Ea = E. aerogenes,∗ MβL P = metallo-β-lactamase-producing Pseudomonas aeruginosa, MβL A = metallo-β-lactamase-producing Acinetobacter baumannii, VRE = vancomycin-resistant Enterococcus, VRS = vancomycin-resistant S. aureus, MDR-S = Multidrug resistant Staphylococcus aureus.

E. aerogenes has been changed to Klebsiella aerogenes.

Chart 1

The above chart shows the number of plants with potential antimicrobial properties collected from each country during the period of 2006–2020.

The plant-derived extracts mentioned in this review were prepared in deionised water and/or diverse organic solvents such as methanol, chloroform, hexane, ethyl acetate, and so on. Alcoholic extracts of ethanol and methanol were the most common extracts used and they showed the highest antimicrobial properties. Antimicrobial assays such as Kirby Bauer Disc Diffusion and Agar well diffusion were performed to determine the Minimum Inhibitory Concentration (MIC) to test the effectiveness of the extracts in MDR bacterial strains. MIC values of the extracts of the same solvent were varied even though all the extracts possessed similar antibacterial efficacy. This was seen because the bacterial inhibition activity is majorly dependent on the bioactive compound present in the extract. So, a difference in MIC between two plant extracts can be attributed to the presence of a different bioactive compound or different concentrations of the same bioactive compound. These bioactive compounds are essentially phytochemicals such as flavonoids, tannins, coumarins, triterpenes, alkaloids, phenylpropanoids, sterols and terpenoids.

Most of the plants showed specific inhibitory effects against one or two members of ESKAPE. However, a few displayed significant broad-spectrum antibacterial activity. These were: and

Therefore, it is vital to perform additional chemical analysis of the aforementioned plant extracts to determine their chemical composition and pin-point the exact phytocompounds responsible for antimicrobial activity. The plant extracts should be subjected to a series of pharmacological tests to ascertain their in vivo efficacy, cytotoxicity, interactions and any harmful side-effects.

Conclusion

Emergence of “superbugs” is a serious health problem due to escaping of antibiotics used for their treatment. Therefore, there is a need for the medicinal plants being exploited as a source for alternative medicines .

However, further research needs be carried out regarding plant-derived active principles, for this knowledge to be translated into potential therapeutic drugs.

Declarations

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement

Data included in article/supp. material/referenced in article.

Competing interest statement

The authors declare no conflict of interest.

Additional information

No additional information is available for this paper.