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5
Explor Anim Med Res,
Vol.7, Issue - 1, 2017, p. 05-10 ISSN 2277- 470X (Print), ISSN 2319-247X (Online)
Website: www.animalmedicalresearch.org
Editorial
ALTERNATIVE TO ANTIBIOTICS - PREPARATION FOR POST
ANTIBIOTIC ERA
All the living entities of our planet are struggling
continuously for their existence. Starting from the minute
viruses, the fungus, bacteria, protozoa, parasites, plants
and animals of various differentiated species are
struggling for their existence and multiplication. In the
way of such struggle, as a part of evolution, many
microorganisms developed their system to secrete some
antibacterial chemicals which are identified by some
scientists and used as antibiotics. Due to uncontrolled
use of these chemicals, the susceptible organisms get
ample opportunity to alter their old systems and to
develop some new system to bypass the detrimental effect
of those chemicals. It is called microbial resistance. In
many cases, that power of resistance is transmissible
vertically among the same species and horizontally
between other species of organisms (Pattanayak 2011).
That ultimately causes some very serious problems like
development of Superbugs-organisms resistant to all
available antibiotics. Those are becoming a threat to the
human civilization!
As man is the most intelligent species of the globe and
wants to use all the resources for existence and
multiplication of their own species, there is always a
pressure to find out the means to overcome anything
against such targets. To combat the problems of antibiotic
resistance and for searching of alternatives of antibiotic
use, various studies are going on throughout the world.
The studies can be categorized in some groups.
i) Alteration and/or addition of some new chemicals with
the presently available anti microbial substances to
bring back their potency.
ii) Searching of some new means of attack on harmful
micro organisms by use of other microorganisms or
their products.
iii) Acceleration of immunity power of human or animals
by using the tools present in the microorganisms.
iv) Use of some new types of substances and procedures
against microorganisms which were not previously
used.
v) Use of antimicrobial, immune-stimulant and other
related substances developed in higher species through
evolution.
i) Alteration and/or addition of some new chemicals
with the presently available antimicrobial
substances to bring back their potency.
Penicillins were the first group of antibiotic, and
resistance against that group of antibiotic noticed first.
The resistant microbes produced beta lactamase enzymes
for that purpose. To overcome the problem, some
chemicals (Clavulanic acid, Sulbactam, Tazobactam etc.)
were added with that group of antibiotics. These
chemicals are not having any anti-microbial action, but
these can assist the antibiotics to overcome the resistance
of the microbes. Afterwards, some other ways were
searched out (bacterial efflux inhibition agents, use of
analogue of antibiotics etc.) to overcome the resistance
of the microorganisms (Pattanayak 2011). But ultimately
it remains a common trend that after effective use for a
few years, the efficacy of these alterations becomes
reduced gradually due to the modification of resistance
mechanism of the micro organisms. So, even continuous
searching and development of such chemicals as well as
prolongation of life of presently used antimicrobials, the
actual efficacy of such procedures becoming shorter
lasting day by day.
ii) Searching of some new means of attack on
harmful microorganisms by use of other micro
organisms or their products.
Antimicrobial peptides: Various plants, animals and
fungi have vastly different immune systems, but all make
peptides (small proteins) that can destroy bacteria. Many
amphibian and reptile species developed peptides which
can kill many pathogenic microorganisms. These peptides
are under study for their therapeutic use as effective anti-
microbial agents (Readon 2015).
The host defense peptides (small, natural peptides) and
innate defense regulators (small, synthetic peptides) have
indirect antimicrobial effects. They primarily act by
increasing expression of anti-inflammatory chemokines
and cytokines, and reducing the expression of pro-
inflammatory cytokines. The anti-biofilm peptides
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Exploratory Animal and Medical Research, Vol.7, Issue 1, June, 2017
specifically inhibit bacterial biofilm formation have been
identified and are in preclinical developmental stage.
(Czaplewski et al. 2016).
Phage therapy: Phases are the viruses that can attack
and kill bacteria. Study to use the efficacy of such viruses
therapeutically against pathogenic bacteria is very old.
As each type of phase generally attacks only one type of
bacterium, so during clinical use all the other harmless
bacteria left unharmed. As phages are abundant in nature,
researchers assume to get ready replacements for any
therapeutic strain that bacteria evolve to resist.
Phages secrete enzymes (lysins) to destroy the cell wall
of a target bacterium and are potential replacements for
antibiotics because of their direct antibacterial action, and
as adjuncts because they act to reduce bacterial burden,
weaken biofilms, or both. Research shows that lysins are
more active against Gram-negative pathogens. Studies
on the therapeutic efficacy of Wild-type bacteriophages
as well as Genetically Engineered bacteriophages are
going on (Czaplewski et al. 2016).
Bacteriocins: These are some toxins produced by
microbes to inhibit the growth of similar or closely related
bacteria. Bacteriocins are structurally, functionally and
ecologically very diverse in nature. These can exhibit
significant potency against other bacteria (including
antibiotic-resistant strains), are stable and can have
narrow or broad-spectrum activity. Bacteriocins can even
be produced in situ in the gut by probiotic bacteria to
combat intestinal infections (Cotter et al. 2013). The main
bacteriocins identified from gram negative bacteria are
Microcins, Colicin-like bacteriocins and Tailocins. The
gram-positive bacteria derived bactericins are classified
into various groups according to their size and some other
characters. Nisin and other Lantibiotics are grouped under
Class I. The heat stable Class II group includes a subgroup
which is having very good potential for use in the field
of food preservation and medical applications. Example
of that subgroup is Pediocin PA-1 (Heng et al. 2007).
Other main bacteriocins of other subgroups are
Lactococcin G (Nissen-Meyer et al. 2009), Enterocin AS-
48, Aureocin A53 (Netz et al. 2002), Aureocin A70 (Netz
et al. 2001). Lysostaphin is a representative bacteriocin
of Class III type (Bastos et al. 2010); Sublancin and
Glycocin F belong to the complex type IV bacteriocin
(Oman et al. 2011, Stepper et al. 2011).
iii) Acceleration of immunity power of human or
animals by using the tools present in the micro
organisms.
Use of antibody: Antibodies that bind to and inactivate
a pathogen, its virulence factors, or its toxins were widely
considered one of the alternative approaches most likely
to have major clinical impact. Antibodies are considered
as safe or low risk measure with a high degree of technical
feasibility (Czaplewski et al. 2016).
Immune stimulation: Successful antimicrobial
therapy depends on impose of an appropriate immune
response. Immune stimulation may be considered as a
potential adjunct approach along with antibiotic therapy.
Orally used bacterial extracts are used to reduce the
incidence of respiratory tract infections in some at-risk
groups. Further clinical trials to substantiate their efficacy
in other populations would encourage wider use. The
mechanisms by which these extracts might work are
unclear. Targeted interventions could be devised once
these mechanisms are understood. New focused research
also has been initiated on assessment of repurposed drugs
for immune stimulation rather than assessment of early
translational research in this specialty (Czaplewski et al.
2016).
Vaccination: From the time of Edward Jenner and Luis
Pasteur, research related with immunization of human or
animals against serious disease-causing microbes are
going on with a history of huge success. The
immunization procedures depend on some basic
principles. It is achieved by introducing live, generally
attenuated infectious agents or inactivated agents or their
constituents or their products in the living body so that
body protective mechanism can develop power to resist
the attack of the original pathogenic micro organisms in
future (Harrison 2008). But anybody can not be made
immunized against each and every type of organisms
which can cause disease by that method.
The long established investment in vaccines for new
targets should continue to substantially reduce the
incidence of infection and the need for antibiotics
(Czaplewski et al. 2016).
iv) Use of some new types of substances and
procedures against micro organisms which were not
previously used.
CRISPR: It is a gene-editing technique based on a
strategy that many bacteria use to protect themselves
against phages. Researchers are turning that system back
on itself to make bacteria kill themselves.
Normally, the bacteria detect and destroy invaders such
as phages by generating a short RNA sequence that
matches a specific genetic sequence in the foreign body.
This RNA snippet guides an enzyme called Cas 9 to kill
the invader by cutting its DNA.
Scientists are now designing CRISPR sequences that
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target genomes of specific bacteria, and some are aiming
their CRISPR kill switches at the bacterial genes that
confer antibiotic resistance (Readon 2015).
Metals: Metals like copper and silver are the oldest
antimicrobials. They were favored by Hippocrates in the
fourth century BC as a treatment for wounds, and were
used even earlier by ancient Persian kings to disinfect
food and water. In the contemporary research, some
groups are exploring the use of metal nanoparticles as
antimicrobial treatments. Because metals accumulate in
the body and can be highly toxic, their use may be
restricted mostly to topical ointments for skin infections.
An exception is gallium, which is toxic to bacteria that
mistake it for iron, but is safe enough in people to be
tested as an intravenous treatment for lung infections.
Pilot studies found that the metal was moderately
successful at breaking down microbial biofilms in the
lungs and improving patients' breathing (Readon 2015).
Probiotics: Probiotics are some selected
microorganisms administered orally. These can confer a
health benefit to the host when administered in adequate
amounts. A defined mixture of bacteria or the use of non-
toxigenic spores of Clostridium difficile may provide
therapeutic and prophylactic therapies that can improve
current clinical practice for the treatment of C. difficile
associated diarrhea and antibiotic-associated diarrhoea
(Czaplewski et al. 2016).
Other related studies:
Immune suppression: Bacterial infection can lead to
an excessive host innate immune response (ranging from
the systemic inflammatory response syndrome to septic
shock), in which the injury to the host is made much worse
by the host's pro-inflammatory cytokine response.
Selective manipulation of this cytokine response could
potentially be used in combination with antibiotics to
reduce pathogen-induced tissue damage.
Anti-resistance nucleic acids: Antibiotic resistance
genes are often spread by highly transmissible plasmids,
particularly in Gram-negative pathogens. Effective
removal of resistance genes could sensitize bacteria to
conventional antibiotics.
Antibacterial nucleic acids: Use of nucleic acids to
directly kill bacteria is being investigated in both
academia and biotechnology companies. Studies are at
an early stage. At the very least, these methods will
continue to be developed to support fundamental
microbial genetics studies.
Toxin sequestration using liposomes: Pathogens
often secrete toxins that damage mammalian cells and
cause inflammation. Administration of liposomes to act
as decoys for toxin binding has been shown to reduce
damage to cells and reduce disease severity.
Antibiotic-degrading enzymes to reduce selection
of resistance: When antibiotics are eliminated via the
gut, exposure of the normal gut bacteria to the antibiotic
may lead to development of resistance and drive
Clostridium difficile associated diarrhea or antibiotic
associated diarrhea. Studies showed that oral β-lactamase
can destroy β-lactams in the faeces. Demonstration of a
clinical benefit of degrading enzyme administration may
be challenging to the process.
Metal chelation: Bacterial pathogens need zinc,
manganese, and iron ions to fully express their
pathogenicity or virulence, biofilm formation, and
multiple essential enzymatic and metallo-β-lactamase
activities. Metal chelation could prevent these key
processes in pathogens (Czaplewski et al. 2016).
Alphamers: Alphamers are immune modifiers
consisting of a galactose-∝- 1,3-galactosyl-β-1,4-N-
acetyl-glucosamine (Gal) epitope fused to a bacterial
pathogen binding aptamer to redirect endogenous anti-
Gal antibodies to the pathogen and enhance immune
clearance.
Alphamer technology is based on chemically
synthesized molecules redirecting naturally occurring
antibodies to selected pathogens to fight infection. One
end of the molecule binds a surface target of a pathogen
cell using an aptamer, while the other end represent
specific epitopes that attach the circulating antibodies.
Immune stimulation by P4 peptide: Phagocytic
killing of bacteria can be enhanced by P4 peptide - a
chemically synthesized 28 amino acid peptide derived
from the Streptococcus pneumoniae surface exposed
virulence factor PsaA. P4 peptide stimulates opsono-
phagocytic uptake and killing in invasive disease models
of S. pneumonia infection in mice. The combination of
P4 given intra-nasally and IgG given intra-peritoneally
resulted in 100% survival in the mouse model and
significantly reduced bacterial burden. A therapy based
on P4, IgG and antibiotic may be an effective treatment
schedule in future (Czaplewski et al. 2016).
Predatory bacteria: Predatory bacteria can be used
to control other pathogenic bacteria. Many different types
of predatory bacteria have been identified, but the
Bdellovibrio and like organisms (BALOs) show particular
Alternative to antibiotics - preparation for post antibiotic era
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Exploratory Animal and Medical Research, Vol.7, Issue 1, June, 2017
promise. BALOs are motile Deltaproteobacteria that
obligately predate Gram-negative bacteria for energy and
nutrients.The genomes of many BALOs encode numerous
hydrolases (e.g., DNases and proteases), essential for prey
digestion and sufficient for attacking even bacterial
biofilms. It is very important because biofilms pose a
treatment challenge in both human and animal infections
making bacteria less sensitive to antibiotics (Allen et al.
2014).
v) Use of antimicrobial, immune-stimulant and
other related substances developed in higher species
through evolution.
Presently, almost same types of antimicrobial drugs
are used during treatment of various animals as well as
in fishery, horticulture and other related purposes. This
practice requires re-thinking. Use of antimicrobial drugs
may be substituted at least partially for treatment of
herbivorous animals by using juice and pieces of
succulent part of medicinal plants directly (Pattanayak
et al. 2016).
Apart from the golden treasury of texts of various
ancient Indian systems of medicines, many plants and
their different types of extracts, natural products etc. were
recommended for their anti-microbial effects in various
texts and practices throughout the world. Use of plants
for antimicrobial, immune-stimulant and other related
purposes are reviewed by many authors. Plants used in/
as tissue and wound healing (42 plants - Jaiswal et al.
2004, 36 plants - Pattanayak et al. 2013), antiseptic
property (35 plants - Pattanayak et al. 2013) skin infection
(175 plants - Gupta et al. 2010), immune-stimulant effect
(13 plants -Pattanayak et al. 2013) are some examples.
Solvent extracted parts of many of the reported plants
were tested and found to have antimicrobial activities.
But in most of the cases, those plants were tested in vitro
or on the laboratory animals mainly at local applications.
On the other hand, in many websites and blogs, it is
claimed that part of many plants, natural products etc.
are having the power to act as alternative to antibiotics.
These include the following plants, plant parts and natural
products.
Aloe vera, American goldenseal (Hydrastis
canadensis), Bearberry (Uva ursi), Blue flag root (Iris
versicolor), Burdock (Arctiuml appa), Cayenne Pepper
(Capsicum annuum), Chaparral (Larrea tridentata),
Cloves (Syzygium aromaticum), Cryptolepis (Cryptolepis
sanguinolenta), Echinacea (E. purpurea and E.
augustifolia), Eucalyptus (Eucalyptus globules) oil,
Garlic (Allium sativum), Ginger (Zingiber officinale),
Grapefruit (Citrus paradisi) seed extract, Holy thistle
(Cnicus benedictus), Honey, Horseradish (Armoracia
rusticana), Juniper (Juniperus communis), Licorice
(Glycyrrhiza glabra and G. uralensis), Lobelia (Lobelia
cardinalis), Mullein (Verbascum thapsus), Myrrh
(Commiphora myrrha), Nasturtium (Tropaeolum majus,
T. peregrinum and T. speciosum), Oregano Oil (Origanum
vulgare), Poke root (Phytolacca decandra), Red clover
(Trifolium pretense), Sage (Salvia officinalis), Thyme
(Thymus vulgaris), Usnea (Usnea spp.), Wild indigo
(Baptisia australis), Wild thyme (Thymus serpyllum),
Wormwood (Artemisia absinthium), Cranberry
(Vaccinium oxycoccos, V. macrocarpon) juice
(foodmaster.com), Sida (Sida acuta), Alchornea
(Alchornea cordifolia), Bidens (Bidens pilosa), Artemisia
(Artemisia annua), Black pepper (Piper nigrumand, P.
longum) (Buhner 2011), Olive (Olea europaea) leaf
extract, Yin Chiao (Chinese Herbal Remedies), Epi Cor
(dried fermentate of Saccharomyces cerevisiae), Elder
berries (Sambucus nigra) (Mindell and Hopkins 2009),
Coconut (Cocos nucifera) Oil, Forsythia suspensa
(Sisson 2011). Oregon Grape (Berberis aquifolium),
Andrographis paniculata, Manuka honey (European
honey bees foraging on Leptospermum scoparium)
(LoGiudice 2011), Onion (Allium cepa), Turmeric
(Curcuma longa), Cinnamon (Cinnamomum verum) ,
Cardamon (Elettaria cardamomum), oils of Basil
(Ocimum basilicum) and Lavender (Lavandula
angustifolia) (Harrington 2015), Pau d'Arco (Tabebuia
impetiginosa) tea, (www.naturalsociety.com), Propolis
(Bee glue), Sangre de Drago (bright red resin of Croton
lechleri) (Stephanie 2015) etc.
The antimicrobial chemicals developed in various
species of plants are also a part of evolutionary outcome
of the struggle for their existence. It can be assumed that
the mechanism of actions of the antibacterial substances
of herbal or other uncommon origin is different than the
presently used anti microbial substances. So it can be
expected that the targeted micro organisms will have to
get accustomed with such diverse types of molecules
before developing resistance as a part of their struggle
for their existence.
Even if we can get success in overcoming the
dominance of infective organisms, the following points
demand more serious consideration for prevention of
repetition of development of such crucial conditions in
future.
i) A change is required in our consideration of
antibacterial substances as an alternative of the minimum
disease protective requirements like good hygienic
practices, adequate public health awareness, creation of
micro organism free apparatus and environment in the
institutions delivering medical supports to the patients,
unhealthy surroundings of human dwellings and
habitations etc. As an example, it can be said that change
of poor living conditions and unhygienic environment of
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the slums should be considered far more important rather
than the use of anti microbial substances to treat the
preventable bacterial diseases of the slum dwellers.
ii) Reconsideration is needed in the fields like use of
same antimicrobial substances in different species of
animals, birds, fishes etc. for treatment of diseases as
well as use of those in agricultural or horticultural
operations to control microbial infections. Some anti-
microbials may be considered as 'stock' for every species
of animals and plants.
iii) As some alternative, maximum efforts may be given
to use biological resources and to make provision of
biological controls. Different medicinal plants/ plant
extracts may be used for curing of ailments of herbivorous
animals. Toxic plant parts or their component may be
studied to use as biological medicines in agriculture and
horticulture. Elaborative research targeting such goal is
needed.
iv) Maintenance of proper hygienic practices and
nutrition level, decrease in the rate of entry of different
types of toxins in the body directly through food or
indirectly through food chain, immunization and immune
stimulation through herbal medication may be
strengthened to reduce the pressure of use of antimicrobial
substances in every related sector.
Shibabrata Pattanayak
Associate Editor,
Exploratory Animal and Medical Research
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