2013, Pages 11–22
Abstract
Methicillin-resistant Staphylococcus aureus
(MRSA) is currently one of the most common causes of serious
infections, in both hospital and community environments. This type of
resistance was discovered in the 1960s, and now (50 years later) it has
not been possible to develop an effective therapy to fight against it.
This chapter compiles the results of several studies demonstrating the
activity (mainly in vitro) of various extracts, essential oils,
and plant-derived molecules that can act alone or in combination
against MRSA. In addition, natural alternatives (other than from plants)
being studied for the same purpose are described. Finally, the
important role of phytotherapy in the development of new therapies
against multidrug-resistant bacteria such as MRSA is emphasized.
Keywords
- methicillin-resistant Staphylococcus aureus;
- phytotherapy;
- ethnopharmacology;
- plant extracts;
- bacterial drug resistance
Introduction
Following its discovery, penicillin began to be used as a treatment for Staphylococcus aureus
infections in the 1940s, initially providing very good results.
However, just 1 year after the implementation of this antibiotic,
penicillin-resistant strains were identified [1].
Such resistance is caused by the production of plasmid-encoded
β-lactamase. Since the 1950s, there has been a substantial and
continuous increase in penicillin resistance. The use of other
antistaphylococcal drugs, such as chloramphenicol, erythromycin,
streptomycin, sulfonamides, and tetracyclines, led to resistance to
these drugs in S. aureus in the 1950s. The introduction of
methicillin (a semisynthetic penicillin) in 1960 marked a major advance
in the treatment of staphylococcal infections resistant to penicillin;
however, the first strain of methicillin-resistant S. aureus (MRSA) was described in 1961, just a few months after onset of clinical use of the antibiotic [2].
The main resistance mechanism of MRSA is the production of a
penicillin-binding protein (PBP) with lower affinity for β-lactam,
called PBP2a. This resistance is encoded by the mecA gene and
is part of a mobile element located within a pathogenicity island known
as staphylococcal chromosomal cassette mec (SCCmec) [3]. MRSA is resistant to all β-lactams (including carbapenems and cephalosporins) [4]
and usually resistant to aminoglycosides, clindamycin, erythromycin,
quinolones, rifampin, sulfonamides, and tetracyclines, while it is
usually susceptible to glycopeptides [5]. In 1996 in Japan, a strain of MRSA was isolated with reduced susceptibility to vancomycin [6],
exhibiting a minimum inhibitory concentration (MIC) of 8 μg/mL.
Subsequently, isolates with the same characteristics were reported in
other countries. In 2002 in the United States, the first MRSA strain
with high resistance was detected (MIC > 32 μg/mL) that had acquired a
vanA gene identical to that of vancomycin-resistant enterococci [7].
MRSA infection often occurs endogenously in sites with previous disturbance of the
mucocutaneous barrier due to traumatic injury, surgery, intravenous
drug abuse, skin diseases, and intravascular catheterization, among
others. This causes further colonization with MRSA, resulting in
infections of the skin and subcutaneous tissue (abscesses), wound
infections, and intravascular or urinary catheter-related infection. The
spread of bacteria by blood can cause septic shock and severe
metastatic infections such as acute endocarditis, arthritis, meningitis,
myocarditis, pericarditis, pneumonia, and osteomyelitis [8].
As described above, bacteria such as S. aureus
develop resistance mechanisms easily over a short time; this resistance
rate is much higher than the rate of creation or discovery of new
antibiotics, which makes it important to investigate therapeutic
alternatives derived from various sources. Plants represent an important
source of antibacterial molecules, some of which are known and probably
others that are unknown. Consequently, a fourfold increase in the
number of publications since the late 2000s compared with the first 5
years of the 1990s reflects the increased research interest in this
field. In the next sections, some of the most important results of
research studies aimed at combating multidrug resistance in S. aureus with plant-derived compounds are shown.
Plants Extracts with Anti-Methicillin-Resistant Staphylococcus aureus Effects
Antibiotic
resistance of microorganisms is a growing problem in public health. It
is considered as an emerging phenomenon worldwide that has led to the
increased resistance of pathogenic microorganisms involved in the
development of nosocomial and community acquired infections.
However,
in relation to the total number of plant species in the world, the
plants that have already been studied in order to evaluate their
antimicrobial properties represent a tiny amount and a large number of
scientists around the world are studying this phenomenon. This interest
is mainly due to the development of bacterial strains with multiple
resistance to antibiotics, a problem that is as old as the use of
antibiotics itself. Thus, over time researchers have developed several
techniques that enable the study of antimicrobial effects. In order to
demonstrate an effect or activity of a plant against a living organism,
it is necessary to separate the active principle(s) from the inert or
inactive components. The most common way to do this is by exposing small
amounts of plant tissues (fresh or dried) to water or organic solvent,
depending on the nature of compound to be obtained (polar solvents for
hydrophilic compounds and nonpolar for lipophilic compounds), or by
successive extractions using different solvents to obtain different
nature extracts. Another way is to obtain essential oil (EO) of a plant
using techniques such as hydrodistillation [9].
Once
the extracts or EOs are obtained, bioassays may be carried out. This
involves exposing organisms to decreasing concentrations of extract or
EO and determining the MIC. In this procedure, one should take into
account that concentrations > 1 mg/mL (in the case of an extract) may
produce false-positive results; therefore, candidates are those plants
extracts that show antimicrobial activity at < 100 μg/mL [10].
Several methods that can be used to establish the MIC include agar
dilution (plate dilution), microdilution (microtiter wells),
macrodilution (in tubes), and indirectly by agar diffusion, among
others. For these tests, the most commonly used culture medium is
Mueller-Hinton in either agar or broth form (depending on the bioassay
technique). This culture medium is accepted by the Clinical and
Laboratory Standards Institute (CLSI) for evaluating the antimicrobial
susceptibility of most bacterial strains. According to the selected
technique, a specific bacterial concentration is used, but in general
the standard reference is a concentration equivalent to tube number 0.5 in the McFarland scale: this represents a turbidity of 1.5 × 108
colony-forming units (CFU) per mL. This bacterial concentration is also
used established to test antimicrobial susceptibility by the agar
diffusion method. Results are frequently achieved after 18–24-h
incubation at a temperature range of 35–37 °C (the temperatures at which
most pathogenic bacteria thrive) [11].
The
antimicrobial effect may be indicated by the MIC or the minimum
bactericidal concentration (MBC), according to the technique used. Some
researchers also report the IC50 (50% inhibitory concentration) or IC90
(90% inhibitory concentration) values. For extracts, the MIC is
reported in units of mg/mL or smaller. For EOs, the MIC or MBC is
usually expressed in units of μL/mL or % v/v. As mentioned above,
several research groups are working on this issue worldwide. Table 2-1
lists some plants that have been investigated and shown to possess
antimicrobial activities, either as an antibiotic adjuvant or by direct
action against MRSA.
- TABLE 2-1. Selected Plants Whose Extracts and Essential Oils Have Anti-Methicillin-Resistant Staphylococcus aureus Activities
Plant Family Plant part MIC Reference Alchornea cordifolia Euphorbiaceae Leaves 3.1 mg/mL [12] Persea americana Lauraceae Leaves 6.3 mg/mL Solanum verbascifolium Solanaceae Leaves 6.3 mg/mL Rosmarinus officinalis Lamiaceae Leaves 0.13–3.13 mg/mL [13] Thymus vulgaris Lamiaceae Aerial parts 18.5 μg/mL [14] Eucalyptus globulus Myrtaceae Aerial parts 85.6 μg/mL Chaerophyllum libanoticum Apiaceae Fruit 0.25 mg/mL [15] Zataria multiflora Lamiaceae Aerial parts 0.5–1 μL/mL (Eo) [16] Atuna racemosa Chrysobalanaceae Seeds 16–32 μg/mL [17] Cleistocalyx operculatus Myrtaceae Buds 4–16 μL/mL (Ext)
8 mg/mL (Eo)[18] Punica granatum Lythraceae Fruit, pericarp 250 mg/L [19] Tabebuia avellanedae Bignoniaceae Wood 125 – > 250 mg/L Dendrobenthamia capitata Cornaceae Aerial parts 1.25 ± 0.18 mg/mL [20] Elsholtzia rugulosa Lamiaceae Whole plant 1.43 ± 0.13 mg/mL Elsholtzia blanda Lamiaceae Aerial parts 1.32 ± 0.16 mg/mL Geranium strictipes Geraniaceae Root 1.34 ± 0.30 mg/mL Polygonum multiflorum Polygonaceae Root 1.34 ± 0.22 mg/mL Emblica officinalis Euphorbiaceae Seeds Synergy with AMX [21] Nymphaea odorata Nymphaeaceae Stamen Synergy with AMX Hypericum perforatum Hypericaceae Aerial parts 1 μg/mL [22] Ecballium elaterium Cucurbitaceae Fruit 0.19–1.56 mg/mL [23] Arthrocnemum indicum Amaranthaceae Buds 4–8 mg/mL [24] Salicornia brachiata Amaranthaceae Buds 4–8 mg/mL Suaeda monoica Chenopodiaceae Leaves 4–8 mg/mL Suaeda maritime Chenopodiaceae Leaves 4–8 mg/mL Sesuvium portulacastrum Aizoaceae Leaves 4–8 mg/mL Avicennia officinalis Acanthaceae Leaves 2–4 mg/mL Ceriops decandra Rhizophoraceae Leaves 1–2 mg/mL Aegiceras corniculatum Myrsinaceae Leaves 0.5–1 mg/mL Excoecaria agallocha Euphorbiaceae Leaves 0.1–0.2 mg/mL Lumnitzera racemosa Combretaceae Leaves 0.5–1 mg/mL Acanthus ilicifolius Acanthaceae Leaves 2–4 mg/mL Olea europaea Oleaceae Leaves 0.8–12.5% v/v (Eo) [25] Chaerophyllum
libanoticumApiaceae Fruit 0.25 mg/mL (EO) [26] Boswellia spp. Burseraceae Bark 17.3–42.1 mg/mL (oleo-gum resin) [27] Melaleuca alternifolia Myrtaceae Leaves 0.04% v/v [28] - AMX, amoxicillin, Eo, essential oil; Ext, extract; MIC, minimal inhibitory concentration.
As shown in Table 2-1,
various plant families have been shown to possess antimicrobial effect,
indicating that their distribution is ubiquitous. This indicates that
plants from all regions of the world may be natural sources of
antimicrobials, which may therefore generate a wide field of research.
Furthermore,
various different parts of the plants can be studied, ranging from the
seed to the fruit, and even the entire plant. It is important to ensure
that the plant resources used should be quickly renewable and that the
maximum amount of material should be obtained from each plant for
obtaining the extract or metabolite. The leaves are the parts of the
plant that best fulfills these characteristics, because they are the
most abundant elements of the plant and are quickly renewed after
harvesting. Although leaves are the ideal source material, we should not
ignore other parts of the plant, since both the distribution and
concentration of metabolites can vary from one tissue to another.
Regarding
the MIC of extract required to inhibit for MRSA, studies have reported
concentrations ranging from 250 mg/mL to 1 μg/mL. However, it is
important to remember that some authors believe that concentrations
> 1 mg/mL (in extracts) are not significant, since the inhibitory
effect may not relate to the activity of the antimicrobial or
metabolite(s) but may instead be a result of other effects, such as
osmotic pressure exerted by solutes on the bacterial cell walls [10].
Molecules with Anti-Methicillin-Resistant Staphylococcus aureus Activity Derived from Plants
Once
a plant extract is found to have an antimicrobial effect, the next
logical step is to determine which compounds or molecules are involved
in this process. This can be accomplished using separation techniques
such as high performance liquid chromatography (HPLC) or gas
chromatography-coupled mass spectrometry, among others. The basis of the
technique is the same, but some adjustments are made in order to work
with extracts. Sometimes, after identifying the antimicrobial molecule,
modifications are performed to the purified compound in an attempt to
increase its antimicrobial activity [29].
The
wide diversity and large number of molecules that may be contained in a
natural extract raises the possibility that the constituent molecules
may react to generate effects such as synergism or antagonism. Thus,
some individual molecules may have stronger effects than the whole
extract (i.e., there is an antagonist within the extract) or a reduced
effect (i.e., there is a synergistic factor in the extract) [30]. However, Ríos et al. [10] propose that individual molecules that have MICs > 1 mg/mL should not be considered as inhibitors.
Table 2-2
lists some molecules with demonstrated antimicrobial effect against
MRSA. It can be noted that the different MICs reported are almost all in
the range of micrograms per milliliter (μg/mL), but concentrations
expressed in micromoles (μM) are also reported. Micromoles is considered
to be the most appropriate unit for assessing molecules (because of
size variations), but it is confusing to compare micromoles with
concentrations expressed in mg/mL (or similar) units. To avoid
confusion, it is recommended to report molecular concentrations in terms
of μM. Rescaling can be then done by dividing the amount in μg/mL by
the molecular weight of the substance and multiplying this result by
1,000 to obtain μM or μmol/L, which is the same.
- TABLE 2-2. Molecules Extracted from Plants that Have Anti-Methicillin-Resistant Staphylococcus aureus Activity
Plant/part Family Molecule MIC References Rosmarinus officinalis/aerial parts Lamiaceae Carnosic acid 32–64 μg/mL [31] Carnosol 16 μg/mL 4′,7-dimethoxy-5-hydroxy-flavone 16–32 μg/mL 12-methoxy-trans-carnosic acid 16–64 μg/mL Hypericum japonicum/aerial parts Hypericaceae taxifolin-7-O-α-l-rhamnopyranoside 8–64 μg/mL [32] aromadendrin-7- O-α-l-rhamnopyranoside 64–128 μg/mL quercetin-7-O-α-l-rhamnopyranoside > 2048 μg/mL Inula hupehensis/root Asteraceae 8-hydroxy-9,10-diisobutyloxythymol 62.3 μg/mL [33] Calophyllum thwaitesii/NR Clusiaceae calozeyloxanthone 4.1–8.1 μg/mL [34] Calophyllum moonii/NR 6-deoxy-γ-mangostin 0.25 mg/mL Punica granatum/pericarp Lythraceae α-lapachone 62.5 mg/L [35] α-xyloidone 125–250 mg/L Tabebuia avellanedae/wood Bignoniaceae α -nor-lapachone 15.6–31.2 mg/L α -nor-hydroxylapachone 15.6–62.5 mg/L Sophora flavescens/roots Fabaceae Sophoraflavanone G 2–4 μg/mL [36] Kuraridin 8–16 μg/mL Dendrobenthamia capitata/aerial parts Cornaceae Betulinic acid 62.5–125 mg/mL [37] Angelica dahurica/roots Apiaceae C17-polyacetylene falcarindiol 8–32 μg/mL [38] Hypericum perforatum L./aerial parts Hypericaceae Phloroglucin 1 μg/mL [39] Momordica balsamina/aerial parts Cucurbitaceae Balsaminol A 50 μM [40] Balsaminol B 25 μM Balsaminagenin F 100 μM Balsaminoside A 50 μM Karavilagenin C 200 μM 7β-methoxycucurbita-5,24-diene-3β,23(R)-diol 25 μM Psoroma species/NR Pannariaceae Pannarin 8 μg/mL (MIC90) [41] Scutellaria baicalensis/NR Lamiaceae Baicalein 64–256 μg/mL [42] Podocarpus totara/leaves Podocarpaceae Totarol 4 μg/mL [43] Artemisia gilvescens/leaves Asteraceae Secoguaianolide sesquiterpene stereoisomer 1.95 μg/mL [44] Ulmus davidiana var. japonica/NR Ulmaceae Mansonone F 0.39–3.13 μg/mL [45] Sophora alopecuroides/NR Fabaceae Alopecurones A–C 3.13–6.25 μg/mL [46] Garcinia mangostana/pericarp Clusiaceae Rubraxanthone 0.31–1.25 μg/mL [47] Myrtus communis/leaves Myrtaceae Myrtucommulone A 0.5–2 μg/mL [48] - MIC, minimal inhibitory concentration; NR, not reported.
Looking at TABLE 2-1 and TABLE 2-2,
we can see that the entries in the former can be more extensively
compared. This is because the technologies necessary to extract and
purify molecules are expensive and require specialized personnel.
Although this can restrict the development of new antibiotics from
natural plant sources, it is the logical way to develop most studies.
Regarding the type of molecules that can be studied, these belong to different classes but are mainly flavonoids and terpenoids.
Synergy between Natural Products and Antibiotics Used for the Treatment of Methicillin-Resistant Staphylococcus aureus
Synergy
is the effect of the combined action of two or more substances (in this
case antimicrobials), characterized by having a greater effect than
that resulting from the sum of the effects of the individual substances [49].
The
synergistic effect occurs when different constituents of an extract
interact to increase a specific antibacterial effect or when they act on
different targets, thus increasing the possibility of affecting several
vital processes in bacterial reproduction or metabolism. This effect is
most striking when an antibiotic is combined with an agent that
antagonizes bacterial resistance mechanisms (as in the case of
β-lactamase) [50].
Herbal
medicine has the particular feature of providing consumers with
synergistic effects of metabolites contained within extracts and may
even generate effects in different systems, thus contributing to patient
healing by treating several different sets of symptoms. This diversity
is also observed in the mechanisms of action that various phytochemicals have on the multidrug-resistant bacteria. Among them are:
- 1.
- Modification of the receptor or active site (enhancing affinity to the antibiotic);
- 2.
- Enzymatic degradation and modification of bacterial enzymes that degrade antibiotics;
- 3.
- Increased permeability of the outer membrane; and
- 4.
- Inhibition of the efflux pump systems [51].
Several
studies have been carried out to combat multidrug resistance in MRSA
and have demonstrated the synergism between some naturally occurring
molecules and chemotherapeutics to which the bacteria have become
resistant (Table 2-3).
- TABLE 2-3. Molecules and Extracts that have Synergy With Antibiotics Against Methicillin-Resistant Staphylococcus Aureus
Plant Part Type of phytochemical Antibiotic Reference Rosmarinus officinalis Leaves Ethanol extract Cefuroxime [13] Aerial parts Carnosic acid Erythromycin, tetracycline [31] Carnosol Tetracycline Hypericum japonicum Aerial parts taxifolin-7-O-α-l-rhamnopyranoside Ampicillin, ceftazidime, levofloxacin [32] Zataria multiflora Aerial parts Essential oil Vancomycin [16] Sophora flavescens Roots Sophoraflavanone G Ciprofloxacin, erythromycin, gentamicin, fusidic acid [36] Kuraridin Ciprofloxacin, erythromycin, gentamicin, kanamycin, fusidic acid, oxacillin Artemisia herba-alba Leaves Methanol extract Chloramphenicol, erythromycin, gentamicin, Penicillin G [52] Achillea santolina Leaves and Flowers Emblica officinalis Seed Ethanol extract Amoxicillin [21] Nymphaea odorata Stamen Scutellaria baicalensis NR Baicalein Ciprofloxacin, oxacillin [42] Ecballium elaterium Fruit Ethanol extract Penicillin G [23] Psoroma spp. NR Pannarin Gentamicin [41] Podocarpus totara Leaves Totarol Methicillin [43] Stephania tetrandra NR Tetrandrine Ampicillin, azithromycin, cefazolin, levofloxacin [53] Demethyltetrandrine Turnera ulmifolia Leaves Ethanol extract Gentamicin, kanamycin [54] Sophora alopecuroides NR Alopecurones A–C Erythromycin, gentamicin, methicillin [46] Garcinia mangostana Pericarp Rubraxanthone Vancomycin [47] - NR, no report.
As
shown in this table, there are more individual molecules than extracts
studied. This may be explained by the large number of possible
interactions that each of the molecules present in the extract has (some
of which may exhibit antagonistic effects that mask a possible
synergistic effect).
Synergism
has been reported in combination with various antibiotics to which MRSA
has resistance, suggesting that these antibiotics combined with the
studied molecules could be used in the treatment of infections caused by
this pathogen.
The strength
of the studies mentioned here varies according to whether the whole
extract or active molecule was tested, the number of combinations with
different antibiotics, the strain tested (reference or clinical
isolate), and the use of a positive control, among other features.
Regarding the use of a positive control, it is important to note that
these are not always available for all strains of MRSA due to the
mechanism of resistance varying for each antibiotic. A possible control
that could be used for molecules with a potential synergistic effect is
reserpine; this alkaloid acts on resistant bacteria by inhibiting efflux
pumps [55]
and its use should be considered when testing selected antibiotics and
MRSA strains that specifically exhibit this type of resistance.
Other Natural Sources with Effects on Anti-Methicillin-Resistant Staphylococcus aureus
Although
plant extracts and their active molecules are widely studied by
research groups around the world, other groups study alternative methods
to overcome bacteria resistant to multiple antibiotics. Nature has
provided a variety of compounds with potential antimicrobial activity
and these sources are currently being explored with good results. The
following sections provide a brief description of some natural alternatives to plant products that can be used against MRSA.
Small Peptides
It
is known that some peptides have antimicrobial effects; these are
distributed in many living organisms throughout the planet. One peptide
that has given good results both in vitro and in vivo
is the omiganan pentahydrochloride (MBI-226), a cationic peptide
composed of 12 amino acids that interacts with the cytoplasmic membrane
of Gram-positive and Gram-negative bacteria, causing changes in its
polarity with subsequent destruction of the bacteria [56]. This peptide is effective against MRSA at an MIC of ≤ 64 mg/mL [57].
Recently, some studies using peptides generated de novo
have given good results; for example, in 2010 Lee and colleagues
reported that a peptide of 11 residues had an MIC of 5 μg/mL against
MRSA, which makes it more effective than omiganan in vitro [58].
Molecules Derived from Animals
Some
chemically modified molecules produced by animals are utilized as
antimicrobials; such is the case for chitosan (chitin polysaccharide
derived by N-deacetylation),
which has a synergistic effect with β-lactams (ampicillin, oxacillin,
and penicillin). The anti-MRSA activities of two deacetylated forms
(aminoethyl-chitosan 90 and 50) have been studied. Results of this study
showed synergy between aminoethyl-chitosan 50 and the three antibiotics
mentioned above; these synergistic combinations dramatically decreased
the MICs of the antibiotics [59].
Bacteriocins
Bacteriocins
are antimicrobial compounds derived from bacteria that are generated as
a competitive mechanism (antagonism) against other bacteria. An example
of this type of bacterium is Pseudoalteromonas phenolica
O-BC30T, which produces a bacteriocin chemically defined as
2,2′,3-tribromobiphenyl-4,4′-dicarboxylic acid that inhibits clinical
isolates of MRSA with MICs in the range of 1–4 μg/mL [60].
Lactobacilli are also known for their ability to produce such substances; L. acidophilus and L. casei
were reported to generate lactic acid derivatives that act as
bacteriocins, thus inhibiting the growth of MRSA by direct antagonism [61].
Nucleotides
There is such a diversity of molecules with potential antimicrobial activity that even the letters of the genetic code
(i.e., nucleotides) have been shown to possess antimicrobial functions.
A study in mice with burns infected with MRSA demonstrated that
interleukin-10 (Il-10) antisense oligodeoxynucleotides have the capacity to exert a protective role against this microorganism in situ
by acting as a mediator of abscess formation, which limits the
infection and makes it impossible for the bacteria to migrate to the
blood and hence to produce sepsis [62].
Nanoparticles
Since
nanotechnology was established as a field of study with various
applications in science and technology, its use has been increasing
dramatically and some years ago nanoparticles began to be studied as
potential antimicrobial agents. Research into this application has been
increasing and it now has great potential to become a viable alternative
to traditional antimicrobials. For example, studies developed by Nanda
and colleagues [63] tested the activity of silver (Ag) nanoparticles against MRSA, with favorable results.
Another
report described the use of polyacrylate nanoparticles covalently bound
to penicillin, which prevent β-lactamases from inactivating penicillin,
thus maintaining the activity of this antibiotic [64].
As
described in previous sections, research into different therapeutic
alternatives to traditional antibiotics is being carried out using a
range of different sources and technologies, which comprise an important
advance in the fight against multidrug resistance exhibited by some
bacterial pathogens such as MRSA.
Conclusions
As
has been said throughout this chapter, multiple resistance to
antibiotics is a growing public health problem; more specifically, MRSA
represents a high risk of infection in both hospital and community
environments.
Since
the 1980s, the production of new antibiotics has been declining such
that 25 years later it has been reduced by two-thirds [65],
suggesting that we are currently underestimating the ability of
bacteria to generate mechanisms of resistance. The versatility of these
microorganisms puts us at a disadvantage; thus, research into new
sources of antibiotics should be a priority worldwide.
Following
great efforts, different lines of research are now consolidating to try
to solve this problem, and it is evident that several plants contain
compounds that either individually or combined with known antibiotics
are effective against multidrug-resistant bacteria like MRSA.
There
is a need to identify alternative therapies against bacterial
resistance and it is evident that compounds with potential antimicrobial
activities exist in Nature. Evidence for this is provided by the large
number of phytochemicals (extracts and EOs) and isolated molecules with
antimicrobial activity that act in many different ways to combat MRSA
and other multidrug-resistant bacteria.
The
diversity of globally distributed flora provides the investigation of
natural extracts with an almost infinite range of possibilities. Nature
will surely give us the necessary substrates, along with suitable tools
and knowledge, to contribute to the fight against pathogens with
multiple antibiotic resistance.
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