Developing New Antimicrobial Therapies: Are Synergistic Combinations of Plant Extracts/Compounds with Conventional Antibiotics the Solution?

TL;DR: This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field.

Abstract: The discovery of penicillin nearly 90 years ago revolutionized the treatment of bacterial disease Since that time, numerous other antibiotics have been discovered from bacteria and fungi, or developed by chemical synthesis and have become effective chemotherapeutic options However, the misuse of antibiotics has lessened the efficacy of many commonly used antibiotics The emergence of resistant strains of bacteria has seriously limited our ability to treat bacterial illness, and new antibiotics are desperately needed Since the discovery of penicillin, most antibiotic development has focused on the discovery of new antibiotics derived from microbial sources, or on the synthesis of new compounds using existing antibiotic scaffolds to the detriment of other lines of discovery Both of these methods have been fruitful However, for a number of reasons discussed in this review, these strategies are unlikely to provide the same wealth of new antibiotics in the future Indeed, the number of newly developed antibiotics has decreased dramatically in recent years Instead, a reexamination of traditional medicines has become more common and has already provided several new antibiotics Traditional medicine plants are likely to provide further new antibiotics in the future However, the use of plant extracts or pure natural compounds in combination with conventional antibiotics may hold greater promise for rapidly providing affordable treatment options Indeed, some combinational antibiotic therapies are already clinically available This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field

Summary

INTRODUCTION

• Bacteria continue to pose one of the greatest risks to human health.
• Similarly, bacteria have developed resistance to many other commonly used antibiotics [Figure 1].[4].
• Surprisingly, many of the bacteria which cause human disease are also essential to the human microbiome.[6].

A BRIEF HISTORY OF ANTIBIOTICS

• Until the early part of the 20th century, the treatment of pathogenic infections relied on traditional medicines (usually plant material).
• The discovery of penicillin was the start of a new era of treatment options for bacterial infections. [8].
• As a consequence, two main events have occurred in parallel throughout the last century.
• The discovery of antimicrobial agents has steadily decreased to no more than a few antibiotics synthesized or discovered in the last decade.
• The development of alternative treatment methods is crucial and considered by WHO to be perhaps the biggest challenge facing medical science.[5].

Antibiotic function

• Depending on their class, antibiotics may halt the synthesis of proteins and metabolites, disrupt binary fission, or damage the integrity of the cell wall.[16].
• Bacteria can develop resistance innately by selective pressures or acquire the resistance machinery from neighboring microbes.
• Bacteria deploy mobile resistance elements (MREs), including transposons, plasmids, and integrons, carrying the genetic material required to confer resistance but not the genes essential for cell function.
• MREs can be transmitted between bacteria of different phyla either directly between adjacent cells  or indirectly by salvaging intact elements .
• Selective pressures for MREs essential for survival promote the preservation of drug resistance mechanisms in bacterial progeny.[11,17].

EVOLUTION OF BACTERIAL RESISTANCE

• The “Golden Age” of antibiotics saw the development of hundreds of antimicrobials for curing infectious diseases.
• S. aureus infections became far less serious, with mortality rates declining an estimated 80%.
• Several factors contribute to the increase in antibiotic-resistant bacterial strains.
• Numerous pathogenic microbes have acquired multiple drug resistance, including Streptococcus pneumoniae, a causative agent of various common diseases such as otitis media, pneumonia, and meningitis.[15].
• Around two-thirds of all ear infections are bacterial, and approximately, 85% of the cases can be resolved without the need for antibiotic treatment.

Multi-resistant strains of microbes: “Superbugs”

• (a) Antibiotic targets and (b) bacterial resistance mechanisms b a 60 Pharmacognosy Reviews, Volume 11, Issue 22, July-December 2017, also known as Figure 2.
• Thus, the therapeutic options available for these diseases are significantly reduced.
• Certain strains of MDR microbes have also acquired increased virulence and enhanced transmissibility.
• Similarly, S. aureus became resistant to penicillin treatment relatively soon after its discovery.
• The overuse of triclosan in soaps, disinfectants, and clothes detergents has led to the formation of triclosan-resistant pathogenic strains, including MRSA.[27,28].

Resistance mechanisms

• Bacteria have developed numerous methods with which to resist antibiotic action  [Figure  2b].
• The drug insensitivity in antibiotic-resistant bacterial strains is generally due to resistance genes and their downstream effects.
• The genes are transported through plasmids that favor the survival of the bacteria in various destructive environments.
• Often, antibiotics must be modified or used in combination against MDR bacteria to avoid these mechanisms.[32].
• Modified β-lactams,  (e.g.,  methicillin, oxacillin), are immune to degradation by narrow-spectrum β-lactamases.

Bacterial resistance and the environment

• The gastrointestinal system of humans and animals is ideal reservoirs for MDR development.
• Antibiotics fed to livestock may reenter the environment directly when recycled onto crops, soils, and detritus as manure.
• There is a clear correlation between the increase in antimicrobial resistance and the simultaneous increase in morbidity, mortality, and cost associated with disease therapy.[49].
• Tetracycline and nitrofurantoin have proved ineffective, with resistance noted against ampicillin and extended-spectrum cephalosporins[60].
• First identified as an outbreak of Enterococcus faecium and Enterococcus faecalis infections resistant to vancomycin,[69] the resistance was found to be due to the plasmid-borne genes vanA, vanB, and vanC.[70,71].

DISCOVERY OF NEW ANTIBIOTICS: RECENT TRENDS

• As discussed, the discovery of new antibiotics with novel mechanisms of action severely declined during the late 1960s.
• All drugs in development must undergo extensive human trials and any success goes unpublished until the agent is approved for human use. [100].
• Only limited activity is observed towards pathogenic Staphylococcus spp. and Clostridium difficile spp. populations in patients by this formulation.[116].
• Indeed, resistance to Avycaz has already been reported. [118].

ALTERNATIVES: NEW SOURCES OF ANTIBIOTIC THERAPIES

• Vaccination used in conjunction with antibiotics Antibiotics alone are not a sustainable solution for the treatment of bacterial infections.
• Medicinal alternatives are available that show effective antimicrobial activity where antibiotics are not effective, or that work to enhance antibiotic activity in  vivo.
• Vaccines provide a prophylactic solution to treatment.[119] Carbavance (meropenem + vaborbactam) Meropenem + novel boronate β-lactamase inhibitor [113] Plazomicin Aminoglycoside [114] Solithromycin Macrolide  [115].
• This has already been observed in hospitalized children.[123].

Bacteriophage therapy

• Bacteriophages present another alternative in the treatment of antibiotic resistant bacteria.
• Infecting and killing of Shigella spp. with bacteriophage was first observed long before Fleming would first observe the effects of penicillin.[124].
• Furthermore, the majority of follow-up research was conducted in Eastern Europe and not translated into English.
• This treatment modality is promising for some bacterial pathogens, although much more research is required in this field.

TRADITIONAL MEDICINES AND PLANT‑DERIVED ANTIBIOTIC THERAPIES

• Traditional healing systems have relied upon medicinal plants for the treatment of bacterial infections for many centuries.
• These bioactive substances  include tannins, alkaloids, carbohydrates and glycosides, terpenoids, steroids, flavonoids, and coumarins.[130].
• Studies suggest PBAs have a variety of applications against many pathogens.
• A  recent report by the WHO described medicinal plants as one of the best potential sources of new drugs.[130].
• There are still only relatively few plant-derived drugs in clinical use.

COMBINATIONAL ANTIMICROBIAL CHEMOTHERAPIES

• There are several ways in which antimicrobial resistance can be prevented, reduced and/or reversed and using medicinal plant extracts with intrinsic Pharmacognosy Reviews, Volume 11, Issue 22, July-December 2017 65 antimicrobial properties has proven to be a relatively effective method.
• A combinational approach that allows synergistic interaction between plant extracts and conventional antibiotics is arguably the most effective method to combat antibacterial resistance.
• Synergistic evaluation studies examine combinations of two or more drugs in the hopes of achieving an enhanced overall effect which is substantially greater than the sum of their individual parts.[164].
• One drug may neutralize or overwhelm the bacterial resistance mechanisms, repurposing the antibiotic drug by increasing its efficacy.
• There is enough evidence to suggest that the β-lactamase inhibitor may bind irreversibly, contributing to the overall efficacy of the antibiotic component of the combination. [170].

Plant extract FIC A FIC B FIC Interpretation

• S. fruticosa=Salvia fruticosa, S. officinalis=Salvia officinalis, S. sclarea=Salvia sclarea, A. tinctoria=Anthemis tinctoria, C. nobile=Chamaemelum nobile, M. recutita=Matricaria recutita, T. argyophyllum=Tanacetum argyophyllum, T. parthenicum=Tanacetum parthenicum, MICs=Minimum inhibitory concentrations, FIC= Fractional inhibitory concentration Figure 3: (a) An isobologram, used to determine whether drug combinations produce effects that differ from the effects of the drugs used individually.
• Over the last decade, the number of studies examining the synergistic interaction between plant extracts and resistance-prone antibiotics has significantly increased.
• It is possible that the Petalostigma spp. extracts examined in the Ilanko et  al.[183] study may also contain an irreversible β-lactamase inhibitor which functions similarly to clavulanic acid to block the bacterial antimicrobial resistance mechanism.
• Efflux pumps are the main bacterial resistance mechanism which renders tetracycline inactive.[182].

CONCLUSIONS

• The early successes in antibiotic therapy yielded life-saving outcomes and is an example of possibly the most remarkable global scientific advance in modern medicine.
• The effectiveness of antibiotics used against a 68 Pharmacognosy Reviews, Volume 11, Issue 22, July-December 2017 myriad of infectious microorganisms has been severely thwarted by the evolution of microbial resistance, arising as early as a decade following the discovery of penicillin.
• There are numerous other advantages associated with the use of synergistic therapies.
• Such a therapeutic strategy is quite specific, repurposing only a single class (or limited classes) of antibiotic.

Full text

Developing new antimicrobial therapies: Are synergistic
combinations of plant extracts/compounds with conventional
antibiotics the solution?
Author
Cheesman, MJ, Ilanko, A, Blonk, B, Cock, IE
Published
2017
Journal Title
Pharmacognosy Reviews
DOI
https://doi.org/10.4103/phrev.phrev_21_17
Copyright Statement
© The Author(s) 2017. This is an Open Access article distributed under the terms of the
Creative Commons Attribution-NonCommercial-ShareAlike 3.0 (CC BY-NC-SA 3.0) License
(http://creativecommons.org/licenses/by-nc-sa/3.0/) which permits unrestricted, non-commercial
use, distribution and reproduction in any medium, providing that the work is properly cited. If
you alter, transform, or build upon this work, you may distribute the resulting work only under a
licence identical to this one.
Downloaded from
http://hdl.handle.net/10072/355208
Griffith Research Online
https://research-repository.griffith.edu.au

© 2017 Pharmacognosy Reviews | Published by Wolters Kluwer -Medknow 57
Developing New Antimicrobial Therapies: Are Synergistic
Combinations of Plant Extracts/Compounds with Conventional
Antibiotics the Solution?
Matthew J. Cheesman
1,2
, Aishwarya Ilanko
3
, Baxter Blonk
3
, Ian E. Cock
3,4
1
School of hP armacy and Pharmacology, Gold Coast Campus, Grith University, Parklands Drive, Southport,
2
Menzies Health Institute Queensland, Quality Use of
Medicines Network, Queensland 4222,
3
School of Natural Sciences, Nathan Campus, Grith University,
4
Environmental Futures Research Institute, Nathan Campus,
Grith University, Nathan, Queensland 4111, Australia
ABSTRACT
The discovery of penicillin nearly 90years ago revolutionized the treatment of bacterial disease. Since that time, numerous other antibiotics have been
discovered from bacteria and fungi, or developed by chemical synthesis and have become effective chemotherapeutic options. However, the misuse of
antibiotics has lessened the efcacy of many commonly used antibiotics. The emergence of resistant strains of bacteria has seriously limited our ability
to treat bacterial illness, and new antibiotics are desperately needed. Since the discovery of penicillin, most antibiotic development has focused on the
discovery of new antibiotics derived from microbial sources, or on the synthesis of new compounds using existing antibiotic scaffolds to the detriment
of other lines of discovery. Both of these methods have been fruitful. However, for a number of reasons discussed in this review, these strategies are
unlikely to provide the same wealth of new antibiotics in the future. Indeed, the number of newly developed antibiotics has decreased dramatically in
recent years. Instead, a reexamination of traditional medicines has become more common and has already provided several new antibiotics. Traditional
medicine plants are likely to provide further new antibiotics in the future. However, the use of plant extracts or pure natural compounds in combination
with conventional antibiotics may hold greater promise for rapidly providing affordable treatment options. Indeed, some combinational antibiotic therapies
are already clinically available. This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future
research in this eld.
Key words: β‑lactamase, clavulanic acid, efux pump inhibitors, multi‑drug resistance, superbugs, synergy
INTRODUCTION
Despite the advancements of modern medicine, bacteria continue to
pose one of the greatest risks to human health. Since the discovery
of penicillin in 1929 by Fleming,
[1]
microbial-derived antibiotics
have completely revolutionized antibacterial therapy. Indeed,
penicillin became the main therapeutic option for infectious diseases.
Furthermore, that discovery resulted in a new eld of antibacterial
drug discovery from bacteria and fungi which has provided medicine
with a myriad of new, highly eective antibiotic compounds.
However, by the 1940s, widespread use of penicillin resulted in the
emergence of new strains of microbes capable of destroying the
drug and negating its eects.
[2,3]
Similarly, bacteria have developed
resistance to many other commonly used antibiotics[Figure1].
[4]
is
emerging trend is concerning and is considered by the World Health
Organization (WHO) to be perhaps the most urgent issue facing
medical science.
[5]
Bacteria are the oldest and most prevalent organisms on earth. ey are
varied, versatile, and are commensal to all mammals. ey can be both
crucial and detrimental to health, depending on host interactions. Climate,
habitat, ethnicity, genetics, diet, and activity cause the microbiome to
uctuate in diversity and may alter host susceptibility to opportunistic
pathogens. Evolutionarily, humans have learned to coexist with various
microbes that are omnipresent on this planet. Although certain microbes
can be mutualistic, there is a large proportion that are pathogenic and
can cause a myriad of potentially life-threatening infectious diseases.
Surprisingly, many of the bacteria which cause human disease are also
essential to the human microbiome.
[6]
Consuming drugs alters the balance
of microbe populations in the gut and may instigate a range of adverse
eects while still providing treatment for specic diseases. Some bacteria
may persist over susceptible populations by resisting the drug altogether.
Multidrug resistance(MDR), is dened as nonsusceptibility to at least
one agent in more than two of the known categories for antimicrobials.
[7]
Pathogens which are recognized as extensively drug-resistant(XDR) are
susceptible to only two or fewer of the antimicrobial categories, and thus,
pose a substantial threat to human health.
Concurrent with the increased incidence of bacterial resistance to
antibiotics, there has been a corresponding decrease in antimicrobial
Cite this article as: Cheesman MJ, Ilanko A, Blonk B, Cock IE. Developing new
antimicrobial therapies: Are synergistic combinations of plant extracts/compounds
with conventional antibiotics the solution? Phcog Rev 2017;11:57-72.
This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix,
tweak, and build upon the work non‑commercially, as long as the author is credited
and the new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com
Pharmacogn. Rev.
A multifaceted peer reviewed journal in the eld of Pharmacognosy and Natural Products
www.phcogrev.com|www.phcog.net
Access this article online
Quick Response Code:
Website:
www.phcogrev.com
DOI:
10.4103/phrev.phrev_21_17
REVIEW ARTICLE
Correspondence:
Dr.Ian E. Cock,
Environmental Futures Research Institute, Nathan Campus,
Grifth University, Nathan, Queensland 4111, Australia.
E‑mail:I.Cock@grifth.edu.au

MATTHEW J. CHEESMAN, etal.: Synergistic Plant Extract–Antibiotic Combinations
58 Pharmacognosy Reviews, Volume 11, Issue 22, July-December 2017
discovery. is has directed researchers toward alternative therapies,
including traditional plant-based medicines, bacteriophage therapies,
and combinational therapies. is review discusses bacterial resistance
mechanisms and strategies(both common and novel) in the development
of new antibiotic therapies. In so doing, we highlight the use of
plant natural products and plant extracts, particularly in synergistic
combinations, as having particular promise for rapidly developing new,
eective treatment modalities available to combat pathogens resistant to
conventional antibiotic therapies.
A BRIEF HISTORY OF ANTIBIOTICS
Until the early part of the 20
th
century, the treatment of pathogenic infections
relied on traditional medicines(usually plant material). e discovery of
penicillin completely revolutionized the treatment of infectious diseases.
is serendipitous discovery resulted from a chance observation that the
growth of Staphylococcusaureus was inhibited by a blue mold(a fungus
from the Penicillium genus) in culture dishes,
[1]
demonstrating that some
microorganisms are capable of producing substances that can inhibit the
growth of other microbial species. e discovery of penicillin was the start
of a new era of treatment options for bacterial infections.
[8]
From that time,
until the latter part of the last century, there was an exponential increase
in the number of antibiotics discovered. Within decades of discovering
penicillin and the sulfonamides, various other antimicrobial agents
of varying properties were introduced to clinicians.
[9]
Indeed, twenty
new classes of antibiotics were developed in the two decades following
the introduction of penicillin for clinical use, including β-lactams,
aminoglycosides, tetracyclines, macrolides, uoroquinolones, and
cephalosporins. Modied β-lactams and β-lactamase inhibitors provided
eective treatment and management of the entire Enterobacteriaceae
family.
[10]
Another novel class of antibiotics would not be introduced again
until 1989. Each class of antibiotics has a unique core structure(scaold).
Subsequently, many antibiotics have been developed through synthetic
tailoring of these scaolds. e discoveries during the mid-1930s to
the early 1960s determined the chemical scaolds of the majority of
antibiotics used today. Existing antibiotics were subsequently modied to
reduce toxicity, improve their spectrum of activity or cross-assayed to test
increased ecacy with other antibiotics.
[11]
Scaolds of cephalosporins,
penicillins, quinolones, and macrolides constitute almost three-quarters
of the new antibiotics discovered between 1981 and 2005.
[12]
e golden
age of antibiotic discovery ended in the early 1960s, and the evolution
of bacterial resistance has since superseded drug discovery. A timeline
of antibiotic implementation and the rise of drug resistance is shown in
Figure1.
e improper and misuse of antibiotics has resulted in the widespread
development of resistance by many bacterial species.
[13,14]
As a
consequence, two main events have occurred in parallel throughout the
last century. e discovery of antimicrobial agents has steadily decreased
to no more than a few antibiotics synthesized or discovered in the last
decade.
[9]
Simultaneously, antibiotic resistance has rapidly increased,
creating multi-resistant organisms that are becoming dicult to manage
given the current antibiotic treatment regimens.
[15]
e development of
alternative treatment methods is crucial and considered by WHO to be
perhaps the biggest challenge facing medical science.
[5]
Antibiotic function
Antibiotics function to kill bacteria or inhibit their growth in a number
of ways [Figure2a]. Depending on their class, antibiotics may halt the
synthesis of proteins and metabolites, disrupt binary ssion, or damage
the integrity of the cell wall.
[16]
Bacteria can develop resistance innately by
selective pressures or acquire the resistance machinery from neighboring
microbes. Bacteria deploy mobile resistance elements(MREs), including
transposons, plasmids, and integrons, carrying the genetic material
required to confer resistance but not the genes essential for cell function.
MREs can be transmitted between bacteria of dierent phyla either
directly between adjacent cells(conjugation) or indirectly by salvaging
intact elements(transformation). Selective pressures for MREs essential
for survival promote the preservation of drug resistance mechanisms in
bacterial progeny.
[11,17]
EVOLUTION OF BACTERIAL RESISTANCE
e “Golden Age” of antibiotics saw the development of hundreds of
antimicrobials for curing infectious diseases. is eruption of new drugs
approved for human use, together with vaccinations, ended several
Figure1: The timeline of antibiotic development and the evolution of resistance. Blue arrows indicate antibiotic discovery and commercialization events,
whereas gold arrows represent bacterial resistance to antibiotics observed in patients

MATTHEW J. CHEESMAN, etal.: Synergistic Plant Extract–Antibiotic Combinations
Pharmacognosy Reviews, Volume 11, Issue 22, July-December 2017 59
major trends in infectious diseases. Half of all post-birth deaths caused
by Streptococcus pyogenes could be prevented with a 4-day prescription
of penicillin. S.aureus infections became far less serious, with mortality
rates declining an estimated 80%. Other diseases such as impetigo or
leprosy became rare or disappeared entirely in developed countries.
[18]
However, the eectiveness of many of these early antibacterial agents
is now limited due to the development of resistance by many bacterial
strains. Several factors contribute to the increase in antibiotic-resistant
bacterial strains. e use of antibiotics has increased at an exponential
rate throughout many industries.
[4]
Due to high demands, the production
of antibiotics has improved in eciency and lowered in cost. As a result,
these drugs are released into the environment at a signicant rate,
contributing to the selection of resistant strains. Numerous pathogenic
microbes have acquired multiple drug resistance, including Streptococcus
pneumoniae, a causative agent of various common diseases such as
otitis media, pneumonia, and meningitis.
[15]
Around two-thirds of all
ear infections are bacterial, and approximately, 85% of the cases can be
resolved without the need for antibiotic treatment. However, antibiotics
are still prescribed to almost every child in the United States presenting
with an ear infection, further contributing to this resistance. As a result
of misuse, penicillin can no longer be relied on for the treatment of
meningitis caused by S. pneumoniae. is, together with the overuse
or misuse of antibiotics, has inicted various selective pressures on
pathogenic microbes, promoting resistance.
Multi-resistant strains of microbes: “Superbugs”
e number of MDR microbes (commonly known as superbugs) is
increasing at a signicant rate as a result of widespread antibiotic misuse.
Figure2:(a) Antibiotic targets and(b) bacterial resistance mechanisms
b
a

MATTHEW J. CHEESMAN, etal.: Synergistic Plant Extract–Antibiotic Combinations
60 Pharmacognosy Reviews, Volume 11, Issue 22, July-December 2017
ese MDR microbes increase the rate of morbidity and mortality due
to multiple mutations in related diseases.
[19,20]
us, the therapeutic
options available for these diseases are signicantly reduced. Certain
strains of MDR microbes have also acquired increased virulence and
enhanced transmissibility. Tuberculosis currently aects around a third
of the human population.
[21]
Although streptomycin and isoniazid
have previously provided eective treatment for this disease, the
development of resistance was rapid, and XDR strains and totally drug
resistant (TDR) forms of the pathogen have evolved.
[21,22]
Similarly,
S. aureus became resistant to penicillin treatment relatively soon aer
its discovery. Methicillin (the rst designer anti-resistance antibiotic)
was introduced in 1960 in the defense against penicillinases,
[23]
with
the emergence of methicillin-resistant S.aureus(MRSA) arising shortly
thereaer.
[24,25]
e establishment of MRSA within the community may
be due to the overuse of antibacterial-containing substances in common
household and hospital cleaning products to achieve a “super clean”
environment.
[26]
Triclosan is a nonspecic biocide which has been used
in clinics and hospitals for many decades. e overuse of triclosan in
soaps, disinfectants, and clothes detergents has led to the formation of
triclosan-resistant pathogenic strains, including MRSA.
[27,28]
Likewise,
the misuse of various other antimicrobial agents has led to the formation
of many MDR pathogens, and this requires urgent attention before
antibiotic resistance becomes more dicult to control.
Resistance mechanisms
Bacteria have developed numerous methods with which to
resist antibiotic action [Figure 2b]. e drug insensitivity in
antibiotic-resistant bacterial strains is generally due to resistance
genes and their downstream eects. e genes are transported
through plasmids that favor the survival of the bacteria in various
destructive environments. Resistance genes may code for eux
pumps which eject antibiotic from the cells, as well as genes that
induce antibiotic-degrading/inactivating enzymes. ese traits can
be inherited, imported from other pathogens, or may occur through
random mutations in bacterial DNA.
[29,30]
Furthermore, microbes can
avoid antibiotic attack through several other mechanisms. Asummary
of some of the major antibiotic drug classes and bacterial resistance
mechanisms is shown in Table1. Each type or class of antibiotic can be
exposed to greater than one single mechanism of resistance and thus
may develop MDR, XDR, or TDR.
Bacterial resistance mechanisms may work to inhibit membrane
permeability to antibiotics, produce enzymes which neutralize
antibiotics or change the antibiotic target to neutralize the interaction.
[31]
e mechanisms may be specic to a target antibiotic or have a broad
spectrum of activity. Oen, antibiotics must be modied or used in
combination against MDR bacteria to avoid these mechanisms.
[32]
For example, β-lactams (e.g.,penicillin, ampicillin, and carbenicillin)
are oen used in combination with β-lactamase enzyme inhibitors.
Modied β-lactams, (e.g., methicillin, oxacillin), are immune to
degradation by narrow-spectrum β-lactamases. Methicillin-resistant
Staphylococcus spp. utilize extended-spectrum β-lactamases (ESBLs)
to resist the modied β-lactams,
[33]
or mutate their penicillin binding
protein(PBP) to render it unable to bind adequately to penicillin-like
drugs.
[34]
Table1: Antibiotics in clinical use and modes of resistance
Antibiotic class Examples Drug target Resistance modes
β-lactams Penicillins(ampicillin)
Cephalosporins(cephamycin)
Penems(meropenem)
Monobactams(aztreonam)
Peptidoglycan biosynthesis Hydrolysis
Eux
Altered target
Aminoglycosides Gentamicin
Streptomycin
Spectinomycin
Translation Phosphorylation
Acetylation
Nucleotidylation
Eux
Altered target
Glycopeptides Vancomycin
Teicoplanin
Peptidoglycan biosynthesis Reprogramming of peptidoglycan biosynthesis
Tetracyclines Minocycline
Tigecycline
Translation Monooxygenation
Eux
Altered target
Macrolides Erythromycin
Azithromycin
Translation Hydrolysis
Glycosylation
Phosphorylation
Eux
Altered target
Phenicols Chloramphenicol Translation Acetylation
Eux
Altered target
Quinolones Ciprooxacin DNA replication Acetylation
Eux
Altered target
Pyrimidines Trimethoprim C1 metabolism Eux
Altered target
Sulfonamides Sulfamethoxazole C1 metabolism Eux
Altered target

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Developing new antimicrobial therapies: are synergistic combinations of plant extracts/compounds with conventional antibiotics the solution? author" ?

However, for a number of reasons discussed in this review, these strategies are unlikely to provide the same wealth of new antibiotics in the future. This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field. Traditional medicine plants are likely to provide further new antibiotics in the future. 

Q2. What were the effective antibiotics for the Enterobacteriaceae family?

Modified β-lactams and β-lactamase inhibitors provided effective treatment and management of the entire Enterobacteriaceae family.[10] 

Q3. What is the role of the outer membrane proteins in the bacterial resistance to antibiotics?

Loss or modification of these outer membrane proteins may lead to antimicrobial resistance due to reduced membrane permeability and thus, reduced uptake of antibiotics.[176] 

Q4. What is the best-known example of antibiotic synergy?

Perhaps the best-known example of antibiotic synergy is the combination of clavulanic acid (a fungal-derived inhibitor of β-lactamase enzymes) with β-lactam antibiotics. 

Q5. What is the biggest challenge facing medical science?

The development of alternative treatment methods is crucial and considered by WHO to be perhaps the biggest challenge facing medical science. 

Q6. How many cases of ear infections can be resolved without antibiotic treatment?

Around two-thirds of all ear infections are bacterial, and approximately, 85% of the cases can be resolved without the need for antibiotic treatment. 

Q7. What are the main reasons for the development of efflux pumps?

As well as the development of efflux pumps, bacteria may also become resistant to antibiotic action by target-site modification  (preventing the binding of antibiotic) and by drug inactivation. 

Q8. What is the main reason why the majority of the developing world relies on traditional medicines derived?

80% of the developing world relies on traditional medicines derived from medicinal plants as their primary health-care modality. 

Q9. What is the effect of isoflavones on berberine?

The isoflavone allows a greater concentration of berberine to accumulate in S. aureus cells by inhibiting the efflux mechanism (MDR pump). 

Q10. What is the role of plant extracts in antimicrobial resistance?

Plant extract/antibiotic combinations not only contribute to and enhance the overall antimicrobial effect, but can also act as resistance modifying/modulating agents. 

Q11. What is the main argument for the use of plant compounds in the treatment of microbial infections?

the ability of plant compounds to “re-purpose” conventional antibiotics in the treatment of microbial infections may significantly impact global health in terms of combatting resistant pathogenic microorganisms. 

Q12. What is the role of clavulanic acid in antimicrobial therapy?

Clavulanic acid is a weak β-lactam with negligible intrinsic antimicrobial activity on its own despite sharing a similar β-lactam ring with other β-lactam antibiotics. 

Q13. What is the effect of the -lactamase inhibitor on the bacterial resistance?

It is possible that the Petalostigma spp. extracts examined in the Ilanko et  al.[183] study may also contain an irreversible β-lactamase inhibitor which functions similarly to clavulanic acid to block the bacterial antimicrobial resistance mechanism. 

Q14. What is the main argument for the use of plant extracts?

The evidence is accumulating that the use of plant extracts enhance the antibacterial activity of conventional antibiotics, serving to repurpose these compounds rather than replacing them. 

Q15. What is the common method of removing antibiotics from the cells?

These efflux pumps are encoded chromosomally and utilized to rapidly remove antibiotics that have entered the bacterial cells, thus rendering them resistant to the effects of the antibiotic. 

Q16. How can MREs be transmitted between bacteria?

MREs can be transmitted between bacteria of different phyla either directly between adjacent cells (conjugation) or indirectly by salvaging intact elements (transformation). 

Q17. How many species of plants have been examined for antimicrobial properties?

of the approximately 422,000 plant species worldwide, it is estimated that only a small portion  (1%–10%) of the estimated total number of herbal medicines derived from these species have been examined for antimicrobial properties. 

Q18. What is the significance of the interaction between PBAs and MRSA?

A significant interaction relevant for clinical infections is the bactericidal effects on MRSA demonstrated by a variety of PBAs. 

Q19. What is the recent and widely accepted method of interpreting synergistic results?

the most recent and widely accepted method is the use of fractional inhibitory concentration index  (ΣFIC)  (derived from minimum inhibitory concentration  [MIC]) and isobologram analysis [Figure 3a] in the interpretation of synergistic results.