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T.O. Lawal. et al. Medical Research Archives vol 6, issue 1, January 2018 issue Page 1 of 22

RESEARCH ARTICLE

NATURAL PRODUCTS AND TRADITIONAL MEDICINES FOR THE TREATMENT OF MULTIDRUG RESISTANT BACTERIA Authors T.O. Lawal1,2, N. Raut2,3, SM Wicks4, G.B. Mahady2 Affiliations: 1Department of Pharmaceutical Microbiology, * Correspondence author: University of Ibadan, Ibadan, Nigeria Gail B. Mahady, Ph.D. 2Department of Pharmacy Practice, College of Department of Pharmacy Practice Pharmacy, PAHO/WHO Collaborating Centre College of Pharmacy, University of Illinois at for Traditional Medicine, University of Illinois Chicago at Chicago, Chicago, IL, USA, 60612. PAHO/WHO Collaborating Centre for 3Department of Pharmaceutical Sciences, Traditional Medicine Rashtrasant Tukadoji Maharj Nagpur 833 S. Wood St, MC 877 University Nagpur-440033 India. Chicago, IL 60612, U.S.A. 4Department of Cellular and Molecular Phone (312) 996-1669 Medicine, Rush University, Chicago, IL, USA Fax (312) 413-5894 60612. Email: [email protected];[email protected]

Abstract: Multidrug resistant microorganisms (MDROs) have been responsible for numerous outbreaks of infectious epidemics, and pose a serious threat to global health. The lack of effective therapies for MDROs, coupled with a reduced number of antimicrobial drugs in the pharmaceutical pipeline to treat these infections, demonstrates the urgent need for research in this area. Of the resistant Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Pseudomonas aeruginosa and multidrug-resistant tuberculosis (MDR-TB) continue to be the most problematic, however, reports of vancomycin-resistant Staphylococcus aureus (VRSA) infections are also increasing. For highly-resistant Gram-negative bacteria, vancomycin-resistant Enterococci (VRE), multidrug-resistant (MDR) carbapenemase-producing Klebsiella pneumoniae and MDR-Acinetobacter baumannii are most important, as these bacteria are often only susceptible to older antimicrobial agents, such as the polymyxins that have a higher adverse event profile. Taken together, these data demonstrate that there is an urgent need for new antibiotics and combinations of drugs to treat emerging MDR bacteria. Due to the lack of interest of pharmaceutical companies in the research and development of new antibiotics, research in the field of natural products has increased. Thus, there is an increasing body of scientific evidence suggesting that specific marine, fungal and medicinal plant extracts, as well as traditional medicine formulas and pure compounds are active against specific MDR-bacteria. Where active, these natural products should be further investigated for possible development as clinical agents. This review focuses on recently published data for natural products active against MDR bacteria and evaluates some of the in vitro data. Key words: Acinetobacter, antibiotics, antimicrobial, botanicals, eathnomedicine, medicinal plants, methicillin-resistant Staphylococcus aureus, natural products, marine, multidrug resistant organisms, traditional medicine, Vancomycin-resistant Enterococci, Klebsiella pneumoniae

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1.0 Introduction development of new antibiotics.2 Unfortunately, The global emergence of multiple drug the bottom line is that new antibiotics, although resistant pathogenic organisms (MDROs) they are critical to overall public health and continues to be a serious public health threat due to welfare, are just not as lucrative of an investment the lack of effective antimicrobial agents for when compared with other drugs. Thus, for the treatment, and a paucity of new antibiotics in the past 20 years only a few companies including, pharmaceutical pipeline.1-3 Globally, the increase AstraZeneca, GlaxoSmithKline, Merck, Johnson & in MDR infections has caused millions of deaths Johnson, and Pfizer/Wyeth have developed new annually, with > 1M deaths annually due to antibiotics past the phase 1 clinical trial stage.6 resistant Shigella and Mycobacterium Interestingly, there has never been a successfully tuberculosis.3 In the United States, MDR bacteria researched and developed antibiotic by any are responsible for > 23,000 deaths and ~ 2M life- government agency, including the National threating infections annually, of which resistant Institutes of Health.6 Thus, instead of the big Clostridium difficile, Enterobacter species, and Pharma taking the lead in this critical and seriously Neisseria gonorrhoeae are now considered ―urgent complicated issue, much of the development is threats‖.4-5 For example, C. difficile infections may being performed by small pharmaceutical and cause life-threatening diarrhea in hospitalized biotech companies, and academic institutions, with patients, who have been recently treated with the exception of Japan, where the large antibiotics.4 In 2015, the Centers for Disease pharmaceutical companies still play a central role Control (CDC) reported that C. difficile was in antibiotic development.6 Therefore, there are responsible for as many as 500,000 infections in plenty of opportunities for researchers interested in the USA in a single year, causing ~15,000 deaths.5 this topic to be involved at the academic level, as The CDC predicts that these numbers will continue much of the scientific research on natural products to increase as the list of resistant bacteria continues is being performed in academic institutions. to grow with Staphylococcus aureus resistance to methicillin and vancomycin, multidrug-resistant 1.2 Natural Products for the treatment of Klebsiella pneumoniae, vancomycin-resistant Multidrug Resistant Organisms Enterococcus (VRE), as well as resistant Plants, animal and marine natural products Pseudomonas aeruginosa, Acinetobacter have always played a role in traditional medicine baumannii and Mycobacterium tuberculosis, all in for millennia, and have made significant need of more effective therapies. Thus, there is an contributions to human health.7-10 Man has used urgent need for the research and development of natural products derived from plants, marine new antimicrobial agents, and combinations of organisms, fungi, animals and minerals to treat all drugs, to treat these life-threatening infections. diseases, including infectious diseases.7-10 Review of the scientific and medical literature suggests 1.1 Lack of interest in developing new that there are thousands of published papers antimicrobial agents describing the antimicrobial effects of bacteria, With so many drug resistant bacteria plant extracts, marine and fungal organisms. Data causing significant morbidity and mortality from the PubMed, Google Scholar and the worldwide it is difficult to understand the lack of Napralert databases (data from 1975 to 2017) interest on the part of pharmaceutical companies to suggest that there are as many as 68,000 reports develop new antibiotics. Since 2004, < 2% of all describing the antimicrobial effects of natural new clinical drugs developed were antibiotics.6 products, and > 2000 reviews on the subject, The reasons for the lack of interest in the research including reviews on Actinomycetes, medicinal and development of new antibiotics appears to be plants, marine products, fungi as antibacterial economic. Antibiotics are less profitability than agents.11-12 In terms of MDR organisms, there are drugs used to treat chronic ailments; prescribing almost 5000 reports in PubMed alone concerning habits suggest that newer antibiotics would only be the effects of natural products on a wide range of prescribed for resistant infections, thereby limiting MDR organisms. The primary focus of these initial investment returns; and the development of invesigations has been determining the in vitro generics is always an issue.2,6 Increased antibacterial activities against methicillin-resistant governmental regulation, economics and scientific Staphylococcus aureus (MRSA), vancomycin- challenges have also not been conducive to the intermediate and resistant S. aureus (VISA and

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VRSA), Klebsiella pneumoniae, vancomycin- plants, fungi and marine organisms that have been resistant Enterococcus (VRE), as well as resistant recently tested and have in vitro activity against Pseudomonas aeruginosa and Mycobacterium MDROs, that may be potential candidates for species.13-19 For example, a recent review of plants research and development as new drugs for the used in traditional medicine from India suggests treatment of MDR bacteria. that there are ~120 plant families, and as many as 130,000 different plant species with medicinal 2.0 Methicillin Resistant Staphylococcus effects, including activities against bacterial aureus (MRSA) infections.17 Many of these plant species have at Drug resistance of MRSA continues to be least in vitro activity against MRSA, including problematic worldwide, and is a serious threat Acorus calamus, Lawsonia inermis, Hemidesmus even in community settings.20 MRSA infections indicus, Holarrhena antidysenterica, Punica are commonly observed in skin, soft tissue, bone, granatum, Plumbago zeylanica, Camellia sinensis, joints, and in patients with indwelling catheters or Delonix regia, Terminalia chebula, Emblica prosthetic devices. Patients with MRSA tend to officinalis and Terminalia belerica.17 However, have poorer clinical outcomes than patients one of the primary stumbling blocks to the infected with methicillin-sensitive S. aureus progression of this research remains the same as it strains. Serious MRSA infectious may lead to was almost 10 years ago, there is still a significant serious, life threating infective endocarditis (IE), lack of rigorous animal studies or controlled septic arthritis, and osteomyelitis. Complications clinical trials for naturally occurring antibiotics.7,9 of these infections such as sepsis and septic In addition, the methods used in many in vitro resistance to first-line drugs are common in publications are not standardized, or are using old healthcare facilities and community clinics.20 It has methods such as ―zone of inhibition‖ instead of been suggested that patients presenting with validated minimum inhibitory concentrations MRSA infections are ~64% more likely to die than (MICs) and/or minimum bactericidal those with infections caused by methicillin concentrations (MBCs). Other issues include high susceptible S. aureus.20 We have previously ―active‖ concentrations at which natural products reported on numerous plant species also having in show efficacy, many at supra-physiological vitro effects against MRSA.7,9 More recent data on concentrations, that would not likely result in some of the plant, marine and fungal species, as activity in vivo. This view will focus on the more well as naturally occurring compounds that are recent data describing the in vitro of natural active against MRSA are detailed in Tables 1 and products as potential antibacterial agents for 2. antibiotic resistant bacteria, including MRSA, VRSA, VRE, Klebsiella, Pseudomonas and Mycobacterium ssp. We will highlight some of the

TABLE 1. Plant and marine organisms and purified compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA).

Organism/compound Family Extract/compounds MIC/MB Reference C Alstonia boonei Apocynaceae Leaf, bark/Echitamine, echitamidine, 128 μg/mL 21, 22 voacangine, akuammidine, N- α-formylechitamidine, N- α- formyl-12- methoxyechitamidine Benzylisoquinolone alkaloids Various Tetrandrine and demethyltetrandrine 64-128/256- 23 1024 μg/mL Berberine Various N/A 32-128/64-256 24 μg/mL Bobgunnia madagascariensis Methanol 23-47 μg/mL 25 Caesalpinia sappan Leguminosae Protosappanins A and B 64 (PsA) and 26 128 (PsB) mg/L Cassia obtusifolia Fabaceae Whole plant extract 64 μg/mL 22 Cinnamomum altissimum and Lauraceae Aqueous 19.5/39 μg 27 Cinnamomum impressicostatum /mL Cissus populnea Vitaceae Methanol 94-375 μg /mL 25 Curcuma longa/curcumin Cucurbitacea Ethyl acetate/curcumin 0.125-2 28 e mg/mL Cynodon dactylon Poaceae Chloroform 63 µg/mL 10 Cytisus striatus Fabaceae Ethyl acetate/isoflavones 1 mg/mL 29 Erythrina senegalensis Methanol 12-23 μg/mL 25 Hypericum japonicum/ Hyperiaceae 80% ethanol/ isojacareubin 4-16 /16-64 30 Isojacareubin μg/mL Juncus inflexus Juncaceae Jinflexin B, juncusol, juncuenin D, 12.5-100 31 and dehydrojuncuenin B μg/mL

Lannea acida Anacardiacea Methanol 94-1500 25 e μg/mL Magnolia officinalis/ Magnoliaceae Magnolol/honokiol 16-64 mg/mL 32 Magnolol/honokiol Nuphar japonicum Nymphaeacea Dried rhizomes/6,6′- 1–4 μg/mL 33 e dihydroxythiobinupharidine Paullinia pinnata Sapindaceae Stem Extract 64 μg/mL 34 Penicillium radicum FKI-3765-2 Trichocomac Rugulosin A -C 0.125-64 35 eae μg/mL Piper betle Piperaceae Leaves/Ethanol 78-156 μg/mL 36 Piper sarmentosum Piperaceae Alcohol 50/100 mg/ml 37 Plagiochasma Aytoniaceae Ricardin C 4-8 mg/mL 38 intermedium, Reboulia hemisphaerica/ricardin C Premna resinosa Lamiaceae Dichloromethane 31.25 μg /mL 39 Rotheca myricoides [syn. Lamiaceae Methanol 31.25 μg /mL 40 Clerodendrum myricoides] Salvia miltiorrhiza Lamiaceae TCM 128-256 mg/L 41 Tabernaemontana alternifolia Apocynaceae Aqueous 600-800 42 μg/ml. Tetradium rutacarpa/evocarpine Rutaceae Evocarpine 8-128 µg/mL 43 Tieghemella heckelii Sapotaceae Aqueous, ethanol, ethyl acetate, 45-97 μg/mL 44

ethanol, Talaromyces wortmannii Asphodeloide Flavomannin/talaromannin/emodin/sk 2-16 μg/mL 45 ae yrin Tetradium ruticarpum/evocarpine Rutaceae Evocarpine 8-128 µg/mL 43 Tripterygium wilfordii Celastraceae Tripteryols B 2.95-8.59 46 (±)-5,4'- μg/mL dihydroxy-2'-methoxy-6',6″- 1.06-2.60 dimethypyraro-(2″,3″:7,8)-6- μg/mL methyflavanone, ((2S)-5,7,4'- trihydroxy-2'-methoxy-8,5'-di(3- methyl-2-butenyl)-6-methylflavanone. Urtica dioica Urticaceae Butanol 16.33 mg/mL 47 Waltheria lanceolata Sterculiaceae Methanol 47-188 µg/mL 25 Zanthoxylum nitidum/coumarins Rutaceae Coumarins 8-64 µg/mL 48

EO = essential oil TCM = Traditional Chinese medicine

Table 2. Marine organisms and naturally occurring compounds with activity against MRSA and

Marine organisms Extract/compounds Concentration Reference Actinomycete NPS8920 Lipoxazolidinones A -C 1–2 μg/mL 49 Alteromonas rava SANK 73390 Thiomarinols A-G < 0.01 μg/mL 50 Bacillus sp. Bogorol A 2-10 μg/mL 51 Bacillus sp. MK-PNG-276A Loloatins A-D 0.5–8 μg/mL 52 Marinispora sp. Marinomycins A, B and D 0.13-0.25 μM 52 Marinispora species NPS12745 Lynamicins A - E 1–3 μg/mL 53 Pestalotia sp. strain CNL-365 Pestalone 37 ng/mL 54 Pseudomonas sp. F92S91 Alpha-pyrones 2–4 μg/mL 55 Pseudomonas 2,4-diacetylphloroglucinol 1–8 μg/mL 56 sp. strain AMSN Pseudomonas fluorescens NCIMB Pseudomonic acids A and C NS 57 10586 Pseudoalteromonas phenolica O- Phenolics 1–4 μg/mL 58 BC30 Streptomyces sp. CNQ-418 Marinopyrroles A and B <0.2 M 59 Streptomyces strain, AM045 Actinomycin V 0.1~0.4 μg/mL 60 Streptomyces sp. HKI0381 Abyssomicin E NS 61 Streptomyces platensis TP-A0598 TPU-0037-A - D 3–13 μg/mL 62 Streptomyces lydicus Lydicamycin 6 μg/mL 63 Streptomyces strain N1-78-1 BE-43472 A -D 0.11–0.45 μM 64, 65 Verrucosispora AB-18-032 Abyssomicin C 4–13 μg/mL 66, 67

While many of these plant, marine, constituent 6,6′-dihydroxythiobinupharidine and fungi species have weak activity against (MIC range 1-4 µg/ml); Hypericum MRSA as determined by MICs above 25 japonicum, and its active chemical µg/mL, a few species stand out, having MICs constituent isojacareubin (MIC range 4-16 below 10 µg/mL. For example, extracts from µg/ml); Talaromyces wortmannii and its the fungus, Penicillium radicum FKI-3765-2, active constituent flavomannin (MIC 2 and its active metabolite Rugulosin A (MIC µg/ml); and Tripterygium wilfordii and its 0.125 µg/ml); the aquatic plant, Nuphar active chemical constituent tripteryol B (MIC japonicum extracts and the isolated active range 1-8 µg/ml) all have good activity

Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra T.O. Lawal. et al. Medical Research Archives vol 6, issue 1, January 2018 issue Page 6 of 22 against various MRSA strains (Table 1). In for vancomycin of ≤ 4 µg/mL are sensitive, addition, to many plant and fungal species, while strains with an MIC for vancomycin of there are more than 3,000 naturally occurring 8-16 µg/mL are defined as intermediate compounds isolated and identified from sensitive (vancomycin-intermediate S. marine organisms, some with exceptional aureus, VISA), and isolates having an MIC MRSA activities (Table 2). Compounds of vancomycin ≥ 32 µg/mL are designated derived from marine actinomycetes are resistant (VRSA). Although these standards especially prevalent. However, it has been are followed in the USA and Canada, in suggested that the recovery of Japan, staphylococci with an MIC of 8 microorganisms from the ocean may not µg/mL are considered VRSA.69 mean that the organism is ‗marine‘, as some In 1997, the first VISA strain was organisms may be wash-in components from identified in Japan, indicating the beginning the terrestrial environment.68 None the less, of resistance to vancomycin, and was the marine environment contains novel heralded as the ―doomsday bug‖ because of microflora that remain a comparatively the lack of effective treatments available.70-71 untapped resource for antimicrobial chemical Between the years 2002-2006, the first constituents.68 For an in-depth review of patients with VRSA were reported in the marine natural products with antibiotic United States.72 All of the isolated VRSA activities against MRSA, see the excellent strains were vanA positive and had an MIC review published by Rahman and co- for vancomycin of 512 µg/mL. Each of the workers.68 The organisms listed in Tables 1 infected patients had a medical history of and 2 are just some of the examples of MRSA, as well as an enterococcal infection, hundreds of naturally occurring organisms and most had received vancomycin therapy and purified compounds, many with excellent prior to the development of VRSA.72 The activity against MRSA. These and many staphylococci isolated from these patients more represent examples of naturally contained the mecA gene for methicillin occurring compounds that may also be resistance, as well as a vanA gene that was potential candidates for research and identical to that of vancomycin-resistant development as clinical anti-MRSA agents. Enterococcus faecalis (VRE), suggesting a gene transfer from Enterococcus to the 2.2 Vancomycin Intermediate and staphylococci.72 VRSA is now found in every Resistant Staphylococcus aureus (VRSA) country worldwide. Thus, in a very short By the 1990s, MRSA had become period of time (from 1997 to 2002) S. aureus one of the most pervasive infections went from an organism that was completely worldwide. As a consequence, the use of susceptible to standard of care antibiotics, to vancomycin, a glycopeptide antibiotic that one that was completely resistant to was the primary treatment for severe MRSA treatment.69 Considering the significant infections, increased dramatically.69 morbidity and mortality of VRSA infections, However, the increased use of vancomycin to the search for new safe and effective treat MRSA, led to increasing numbers of antimicrobial agents for VRSA should be clinical isolates with reduced susceptibility to high priority worldwide. vancomycin.69 The National Committee for Reviews of the scientific literature Clinical Laboratory Standards (NCCLS) that show that there are >100 published reports of sets standards to describe sensitivity and medicinal plants with in vitro activity against resistance for bacterium and antibiotics has VISA and VRSA. Table 3 is a summary of defined vancomycin resistance.69 According some of the tested plant species with in vitro to the NCCLS, staphylococci with an MIC activity against VISA and VRSA.

Table 3. Naturally occurring extracts and compounds from plant, fungi and marine species with activities against vancomycin resistant Staphylococcus aureus (VRSA).

Organism/compound Family Extract/compounds MIC/MBC Reference Achillea millefolium Compositae Aqueous alcohol 1.0 mg/mL 73 Achyrocline Compositae Achyrofuran 0.07 μg/ml 74 satureioides Allium ascalonicum Amaryllidaceae Aqueous alcohol 128 μg/mL 73 Armoracia rusticana Brassicaceae Isothiocyanates 666 μg/mL 75 Chrysophyllum Sapotaceae Hexane 0.63–10 mg/ml 76 albidium Nymphae lotus Nymphaceae Ethanol 5-80 mg/mL 77 Plectranthus Lamiaceae Carvacrol 10.25 78 amboinicus/ carvacrol mg/mL/0.5 mg/mL Rosmarinus officinalis Lamiaceae Alcohol 0.156 79 mg/mL/0.312 mg/mL Salvia miltiorrhiza Lamiaceae Cryptotanshinone 2 μg/mL/4 80 μg/mL Tabernaemontana Apocynaceae Aqueous stem bark 600–800 81 alternifolia μg/mL

While the in vitro data for most of these plant classified as enteric Gram-positive cocci in extracts and pure compounds is weak, as the genus, Streptococcus, but then they later many of them have MICs for VRSA above were re-categorized into their own genus, 25 µg/mL, there are again a few plant extracts Enterococcus.82-83 There are more than twelve and purified compounds with excellent different Enterococcus species, however only activity against VRSA. These include two are predominant human pathogenic extracts from Achyrocline satureioides infections, namely E. faecalis and E. (Compositae), and its isolated active faecium.82 Enterococci are now a common compound, achyrofuran (VISA MIC 0.07 cause of nosocomial infections worldwide, μg/ml)74. Also, the traditional Chinese herbal and have long been recognized as an medicine, Salvia miltiorrhiza (Lamiaceae) important cause of bacterial endocarditis.82-83 and its active constituent, cryptotanshinone In the United States, enterococci are the that had an MIC of 2 μg/mL and an MBC of second most common bacteria recovered 4 μg/mL.80 In addition, cryptotanshinone had from catheter-associated infections of the synergistic effects when combined with bloodstream and urinary tract, and from skin vancomycin in VRSA strains, suggesting that and soft-tissue infections.82 These bacteria are combinations of cryptotanshinone and able to survive in hospital environments vancomycin may be feasible for the clinical because they are not generally susceptible to management of VRSA.80 Thus, there are a commonly used antibiotics, and because they number of natural products or natural can actively acquire resistance to common product/antibiotic combinations that might be antibiotics through the process of mutation or feasible for the development of new through the transfer of genetic materials via treatments for both VISA and VRSA. plasmids and transposons.82 Enterococci have a high tolerance to both β-lactam and 3.0 Vancomycin resistant Enterococci glycopeptide antibiotics, and treatment Enterococci are Gram-positive, facultative normally requires one of these antibiotics in anaerobes that are well known to have the combination with an aminoglycoside. ability to survive under harsh conditions.82-83 However, the synergistic bactericidal effects Prior to the 1980‘s Enterococci were between the aminoglycosides and β-lactams

or glycopeptide antibiotics may be lost if discovery and development of new there is high resistance to either antibiotic. antibiotics‖.85 The major objective of Until recently, vancomycin was the primary developing this WHO list was to guide the antibiotic consistently used for the prioritization of incentives and funding, and management of infections caused by MDR help align research and development enterococci. However, Vancomycin-resistant priorities for antibiotics with public health enterococci (VRE) now pose a global threat needs.85 VRE ranks in the high priority to public health and are emerging as some of category on the list. WHO also recommends the most common antimicrobial-resistant that there should be a new emphasis on the pathogens causing nosocomial infections.83-84 discovery and development of novel VRE infections have been associated with antibiotics specifically active against increased length of hospital stays and multidrug- and extensively drug-resistant mortality. The World Health Organization Gram-negative bacteria.85 As a consequence, (WHO) has deemed VRE to be of high there has been an increased effort to test importance in the ―Global Priority list of natural products against Enterococci, antibiotic-resistant bacteria to guide research, including VRE, see Table 4.

Table 4. Plant, fungal, and marine organism extracts with activities against drug resistant Enterococcus faecalis, Pseudomonas aeruginosa, and Klebsiella pneumoniae.

Plant/compound Family Bacterial Strain Concentration Reference

Aframomum citratum Zingiberaceae MDR-Enterobacter, Klebsiella 512-1024 μg/mL 86 pneumonia Allanblackia gabonensis Clusiaceae MDR-Enterobacter, Klebsiella 64-1024 μg/mL 87 pneumonia, Pseudomonas aeruginosa Arnebia euchroma/ butyryl Boraginaceae VRE 3.13 to 6.26 μg/mL 88 alkannin Beilschmiedia acuta Lauraceae MDR-Enterobacter, Klebsiella 16-256 μg/mL 89 pneumonia, Pseudomonas aeruginosa Beilschmiedia cinnamomea Lauraceae MDR-Enterobacter, Klebsiella 64-1024 μg/mL 86 pneumonia, Pseudomonas aeruginosa Bobgunnia madagascariensis Caesalpinaceae VRE 23–47 g/mL 25 Cistus ladaniferus Cistaceae MDR Enterobacter serogenes 0.05 to 0.8 mg/mL. 90 EA289 Clausena anisata Rutaceae MDR-Enterobacter, Klebsiella 128-256 μg/mL 89 pneumonia, Pseudomonas aeruginosa Combretum molle Combretaceae MDR-Enterobacter, Klebsiella 256-1024 μg/mL 86 pneumonia, Pseudomonas aeruginosa

Dichrostachys glomerata Mimosaceae MRD- Enterobacter; Klebsiella 512-1024 μg/mL 86 pneumonia Ecteinascidia turbinate isolated Unknown VRE 0.11–0.45 μM 64 Cyanobacterium Echinops giganteus Asteraceae MDR-Enterobacter, Klebsiella 512-1024 μg/mL 86 pneumonia, Pseudomonas aeruginosa Entada abyssinica Fabaceae Klebsiella pneumoniae 128 μg/mL μg/mL ATCC11296 Kp55 Erythrina senegalensis Fabaceae MDR-Enterobacter 12-24 μg/mL 25 Erythrina sigmoidea/ Fabaceae MDR-Enterobacter, Klebsiella 8 μg/mL 92 neobavaisoflavone pneumonia, Pseudomonas aeruginosa Fagara xanthozyloïdes Rutaceae MDR-Enterobacter, Klebsiella 256-1024 μg/mL 86 pneumonia, Pseudomonas aeruginosa Garcinia mangostana Clusiaceae VRE 3.13- 93 6.25 μg mL Holarrhena Apocynaceae MDR Pseudomonas 40 mg/mL 94 antidysenterica/conessine aeruginosa Khaya senegalensis Meliaceae Aminoside-RE 94 μg mL 25 Mondia whitei Periplocaceae MDR-Enterobacter, Klebsiella 1024 μg/mL 86 pneumonia, Pseudomonas aeruginosa Nauclea pobeguiinii/resveratrol Rubiaceae VRE 32 μg/mL/16 μg/mL 95 Newbouldia laevis Bignoniaceae MDR-Enterobacter, Klebsiella 126-256 μg/mL 89 pneumonia, Pseudomonas aeruginosa Nuphar japonicum/6,6′- Nymphaeaceae VRE 1–4 μg/mL 33 dihydroxythiobinupharidine Olax subscorpioidea Olacaceae MDR-Enterobacter, Klebsiella 256-1024 μg/mL 86 pneumonia Piper betle Piperaceae VRE 19 μg/mL 36 Polyscias fulva Araliaceae Enterobacter, Klebsiella 126-256 μg/mL 89 pneumonia, Pseudomonas aeruginosa Solanum melongena Solanaceae Enterobacter, Klebsiella 512-1024 μg/mL 86 pneumonia, Pseudomonas

aeruginosa Tripterygium wilfordii/ Tripteryols Celastraceae Pseudomonas aeruginosa, VRE 2.95-8.59 μg/mL 96 B Uapaca togoensis Euphorbiaceae Aminoside-RE 94 g/ml 25, 97 Waltheria lanceolata Sterculiaceae Aminoside-RE 94 g/ml 25 Ximenia americana Olaeaceae Aminoside-RE 94 g/ml 25 Xylopia aethiopica Annonaceae Klebsiella pneumoniae 64 μg/mL 86 ATCC11296 Kp63 VRE = Vancomycin-resistant Enterococcus faecalis

From these results in Table 4, of bacteremia, pneumonia, and neonate Arnebia euchroma extracts and the active infections, and resistance of KP to antibacterial compound, butyryl alkannin, carbapenem has spread to globally.99-100 In inhibited the growth of VRE in vitro with an fact, KP is now the most common MIC range of 3.13 to 6.26 μg/mL, suggesting carbapenemase-producing Enterobacteriaceae excellent activity.88 Also, Garcinia (CRKP) globally, causing significant mangostana (Clusiaceae) and Nuphar morbidity and mortality.100 Currently, there japonicum (Nymphaeceae) inhibited the are few antibiotics available for the treatment growth of VRE with MICs of 3.13-6.25 μg of CRKP infections, and therefore the mL and 1–4 μg/mL, respectively, also research and development of new agents to indicating excellent activity.33,93 Furthermore, treat CRKP is also a global priority. Along the traditional Chinese herbal medicine, with KP, Pseudomonas aeruginosa is also an Tripterygium wilfordii and its active important cause of nosocomial infections.99 constituent, Tripteryols B, inhibited the The antibiotics currently used to treat P. growth of VRE with an MIC range of 2.95- aeruginosa, include penicillins, 8.59 μg/mL.96 There are also numerous cephalosporins, carbapenems, and compounds isolated and identified from fluoroquinolones, particularly ciprofloxacin.99 marine organisms, with exceptional activity The aminoglycosides have been used in against VRE (see Table 4), particularly combination with other drugs for the compounds derived from marine treatment of serious pseudomonal infections, Actinomycetes. Thus, along with plant but are not recommended as single entity extracts, marine organisms are an excellent treatment.99-101 Like KP, P. aeruginosa has and untapped source of novel biomolecules become an MDR pathogen associated with with activities against both MRSA and VRE high morbidity and mortality.101 MDR P. that may be useful for further research and aeruginosa causes a wide range of life development of new treatments for these threating infections including pneumonia, infections. sepsis and urinary tract infections.101 Treatment for MDR P. aeruginosa is difficult 3.1 Drug resistant Klebsiella due to the broad range of antibiotic pneumonia, Pseudomonas aeruginosa and resistance. Numerous MDR efflux pumps Acinetobacter baumannii have been identified in MDR P. aeruginosa, While infections caused by Gram- including MexAB-OprM, MexCD-OprJ, positive bacteria may be more prevalent in MexEF-OprN, and MexXY-OprM.101-103 hospital settings, the Gram-negative MexAB-OprM is an efflux pump for Enterobacteriaceae, have by far the highest numerous antibiotics including mortality rate.99-104 Bacteria from the genus fluoroquinolones, β-lactams, tetracycline, Klebsiella are some of the most commonly macrolides, chloramphenicol, novobiocin, isolated bacteria from patients in the trimethoprim, and sulphonamides.101-103 Thus, intensive care units (ICUs) of hospitals.99-100 along with KP, MDR-P. aeruginosa is a Klebsiella pneumoniae (KP) is a major cause serious life threatening infectious agent in

urgent need of new treatments. The data in the research and development of new Table 4 outlines some of the active extracts antimicrobial agents for the management of and pure compounds from plants, fungi and these infections. marine organisms that are active against KP A number of reviews have already and P. aeruginosa. outlined the isolation and characterization of Along with KP and P. aeruginosa, naturally occurring plant-based compounds Acinetobacter baumannii is also a serious with activity against AB up to 2015.108-109 cause nosocomial infections and associated The review by Miyasaki detailed the wide with high rates of morbidity and mortality.104 range of naturally occurring compounds that Acinetobacter baumannii (AB) is a were active against AB108, and the excellent significant cause of bacteremia, pneumonia, review by Tiwari et al.,109 has detailed the meningitis, urinary tract and wound naturally occurring compounds from plant infections, and also of significant concern due extracts that have potent antibacterial to drug resistance.105-106 The wound infections activities against carbapenem resistant strains caused by AB often inflitrate skin and deep of AB. In addition, Abdulhaq110 has outlined soft tissue leading to osteomyelitis, the antibacterial effects of essential oils from bacteremia and other life-threating Arabian plants with activity against AB and complications.105 In addition, AB is the most XDR-AB (Table 5). For example, the common Gram-negative bacillus isolated in essential oils of Acacia arabica, Combretum traumatic injuries to extremities and from aculeatum, Eucalyptus camaldulensis, patients who suffered traumatic injuries, Hibiscus sabdariffa, and Rosmarinus particularly those obtained during emergency officinalis are active against AB and XDRAB situations such as war or earthquakes.105-106 in concentrations below 10 μg/mL (Table Thus, AB has been characterized as a novel 5).110 Furthermore, Intorasoot et al.,111 have and a rapidly emerging clinical pathogen that also reported activities of essential oils from possesses a variety of antimicrobial resistance common spice plants against AB and MDR- mechanisms.106 Due to increasing antibiotic AB. Interestingly, essential oils have been resistance rates, multi-drug (MDR-AB) and used for thousands of years to manage extensively-resistant A. baumannii (XDR- wounds healing and many of these naturally AB) have become a serious threat particularly occurring essential oils appear to speed to immune compromised patients.106 The wound healing, as well as inhibit the growth available treatments for treating MDR-AB of a wide range of MDR bacteria.110-111 Thus, and XDR-AB are extremely limited, and there may be an opportunity to develop the there has been a renewed interest in the older most active essential oils alone or in antimicrobial agents such as rifampin and combination with antibiotics for the minocycline.106-107 However, like CRKP, management of MDR- and XDR-AB. MDR- and XDR-AB are also high priority for

Table 5. Naturally occurring essential oils from plants from Arabia used to treat MDR-AB and wounds. Organism/compound Family Extract/compounds MIC/MBC Reference Acacia nilotica [syn. A. Leguminosae Essential oil <0.39 μg/mL/1.56 Abdulhaq, Arabica] μg/mL 2017 Combretum aculeatum Combretaceae Essential oil 0.78 μg/mL/0.78 μg/mL Abdulhaq, 2017 Hibiscus sabdariffa Malvaceae Essential oil 1.56 μg/mL/3.13 μg/mL Abdulhaq, 2017 Peganum harmala Nitrariaceae Essential oil <0.39 mg/mL/0.78 Abdulhaq, μg/mL 2017 Rosmarinus officinalis Laminaceae Essential oil 3.13μg/mL/3.13μg/mL Abdulhaq, 2017 Tamarix aphylla Tamariaceae Essential oil 12.5 µg/mL/12.5 μg/mL Abdulhaq, 2017

3.2 Drug resistant Mycobacterium deaths as these strains are resistant to the tuberculosis most commonly used TB drugs, isoniazid and Infections caused by Mycobacterium rifampicin.115 Extensively drug-resistant tuberculosis (MTb) also continue to be a tuberculosis (XDR-TB), a form of serious threat to public health worldwide.114- tuberculosis that is resistant to at least four of 115 It is estimated that there are > 10 million the core anti-TB drugs, has now been new cases and 1.5 million deaths annually identified in over 100 countries.118 An due to MTb infections alone.114-117 The estimated 9.7% of people with MDR-MTb continued prevalence of MTb is associated have XDR-TB, and XDR-MTb mortality can with the increase in HIV/AIDS, a lack of new be as high as 40-50%, particularly in cases antibiotic therapies, poor use of anti-TB where the patients are also infected with drugs, as well as the emergence of multi-drug HIV.119-120 Reviews from the scientific and resistant (MDR-TB) and extensively drug medical literature suggest that there are resistant (XDR-TB) strains.115 During the last hundreds of plant, marine and fungal species forty years, resistant strains of MTb have worldwide that have been tested for activity evolved from single drug resistance, to MDR against MTb, and many naturally occurring and extensively drug resistant (XDR), and compounds have been isolated and identified finally now to totally drug resistant (TDR) with activity against MTb, MDR-TB and strains, due to the sequential accumulation of XDR-TB.115,120-121 Table 6 is an overview of resistance mutations.116 WHO estimates that, some of the more recent work in the field in 2014, there were about 480,000 new cases from plant, marine and fungal species, as well of multidrug-resistant tuberculosis (MDR- as isolated natural compounds with promising TB), of which only about 25% were detected activity against MDR- and XDR-TB. and reported.118 MDR-TB requires longer Interestingly, numerous naturally occurring treatment and, treatment tends to be less compounds with excellent activity against effective. Of the MDR-TB cases in 2014, MDR-TB, with MICs below 5 μg/mL (Table WHO estimates that only one half of these 6). These natural products could be used as patients were successfully treated.118 MDR- the basis for further research in animal and TB strains are now reported to be the cause of human studies, or in mechanistic studies. ~480 thousand cases of MTb and > 200,000

Table 6. Naturally occurring extracts and compounds from plant, fungi and marine species with activities against MDR and XDR-MTb.

Organism/compound Family Extract/compounds MIC/MBC Reference Artemisia capillaris Compositae Ursolic acid and 12.5- 123-124 hydroquinone 25 μg/mL Caesalpinia sappan Leguminosae 3- 3.125-12.5 125 deoxysappanchalcone μg/mL Citrullus colocynthis Cucurbitaceae Ursolic acid and 31.2–125 126 cucurbitacin E 2-0-β- μg/mL d-glucopyranoside Cynanchum atratum Apocynaceae (-)-Deoxypergularine 12.5 µg/mL 127 Diospyros anisandra Ebenaceae Plumbagin, maritinone 1.56-3.33 128 and 3,30-biplumbagin mg/mL Kaempferia galanga Zingiberaceae Ethyl p-methoxy- 0.485 mM 129 cinnamate Lentzea kentuckyensis Pseudonocardiaceae Lassomycin 0.41 to 1.65 130 μM Marine fungi Unidentified Vermelhotin 1.5- 12.5 131 µg/mL Marine Streptomyces Actinomycetes Cyclomarin A 0.3 μM 130

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Nonomuraea spp Actinomycetes Ecumicin 0.16-0.62 130 μM/1.5 μM Plumeria rubra [syn Apocynaceae Plumericin and 1.2-2.6 µg/mL 132 P. bicolor] isoplumericin Pterolobium stellatum Leguminosae Chloroform 0.078 mg/mL 133 Tiliacora triandra Menispermaceae Tiliacorinine, 20- 0.7 to 6.2 134 nortiliacorinine and µg/mL tiliacorine

4.0 Conclusion making treatment choices difficult and Globally, antimicrobial resistance is causing serious adverse events.1-4,136-137 The occurring in both Gram-positive and Gram- lack of new antimicrobial agents in negative bacteria, and new efforts have been development to address MDROs is a initiated to harmonize the description and significant problem as many pharmaceutical classifications of these bacteria to assure that companies choose not to develop these drugs surveillance data can be reliably collected due to the lack of financial return on across countries.135 Due to resistance to more investments. As a consequence, the potential than one antibiotic, the treatment of use of natural products against MDROs has multidrug-resistant infections is more been the focus of intensive research, and difficult and complicated, and may require thousands of natural products have been multiple rounds of antibiotic therapies. tested against these organisms, some with Infections caused by MDROs may lead to excellent results. In this work, we have inadequate or delayed antimicrobial therapy, shown that for many of these MDROs, there and tend to be associated with poorer patient are extracts and pure natural compounds with outcomes.1-4,135 To make matters worse, significant activity against MDR bacteria that despite the growing need for new antibiotics could be potentially developed as clinical for the increasing numbers of MDROs, only a agents to treat these infections. In addition, few new antibiotics have been approved for there are many reports of natural products clinical use in the past 20 years.2 having additive or synergistic effects with Of the resistant Gram-positive antibiotics against MDROs that could bacteria, both MRSA and MDR-MTb are perhaps extend the life of common now commonly seen. However, more antibiotics. While there are challenges to the recently, there has been increasing reports of development of natural products, novel VISA and VRSA, as well as VRE, MDR-KB, strategies in antibiotic development and Pseudomonas and Acinetobacter species. All potentially new drug combinations have put of these bacteria represent serious threats to natural products back in the forefront of the public health as they are often only MDRO crisis and will hopefully lead to a susceptible to some of the older and more new era in antibiotic development.2 toxic antibiotics such as the polymyxins,

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