Elsevier

Phytomedicine

Volume 15, Issue 8, 1 August 2008, Pages 639-652
Phytomedicine

Review
Synergism between natural products and antibiotics against infectious diseases

https://doi.org/10.1016/j.phymed.2008.06.008Get rights and content

Abstract

Antibiotics have been effective in treating infectious diseases, but resistance to these drugs has led to the emergence of new and the reemergence of old infectious diseases. One strategy employed to overcome these resistance mechanisms is the use of combination of drugs, such as β-lactams together with β-lactamase inhibitors. Several plant extracts have exhibited synergistic activity against microorganisms. This review describes in detail, the observed synergy and mechanism of action between natural products including flavonoids and essential oils and synthetic drugs in effectively combating bacterial, fungal and mycobacterial infections. The mode of action of combination differs significantly than that of the same drugs acting individually; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries.

Introduction

Infectious diseases are caused by bacteria, viruses, parasites and fungi, and it is due to a complex interaction between the pathogen, host and the environment. The discovery of antibiotics had eradicated the infections that once ravaged the humankind. But their indiscriminate use has led to the development of multidrug-resistant pathogens. Around 90–95% of Staphylococcus aureus strains worldwide are resistant to penicillin (Casal et al., 2005) and in most of the Asian countries 70–80% of the same strains are methicillin resistant (Chambers, 2001). There are considerable reports on the progress of resistance to the last line of antibiotic defense, which has led to the search for reliable methods to control vancomycin-resistant Enterococci (VRE) and S. aureus (VRSA), and methicillin-resistant S. aureus (MRSA). In addition, the synergy between tuberculosis and the AIDS epidemic, along with the surge of multidrug-resistant isolates of Mycobacterium tuberculosis, has reaffirmed it as a primary health threat. Multidrug-resistant TB (MDRTB) is associated with high death rates (50–80%), spanning within a relatively short period of time (4–16 weeks) from diagnosis to death (WHO, 2004). In developing countries, MDRTB has increased in incidence and it interferes with TB control programs.

Plant-derived antibacterials are always a source of novel therapeutics. A quick look at the way nature, especially plants, are tackling the issue of infection will provide a deeper understanding of the methodology, which needs to be adopted for the design and development of novel highly effective antiinfectious agents in general, and antimycobacterials in particular. The scarcity of infective diseases in wild plants is in itself an indication of the successful defense mechanisms developed by them. Plants are known to produce an enormous variety of small-molecule (MW<500) antibiotics – generally classified as ‘phytoalexins’. Their structural space is diverse having terpenoids, glycosteroids, flavonoids and polyphenols. Be that as it may, it is interesting to note that most of these small molecules have weak antibiotic activity – several orders of magnitudes less than that of common antibiotics produced by bacteria and fungi. In spite of the fact that plant-derived antibacterials are less potent, plants fight infections successfully. Hence, it becomes apparent that plants adopt a different paradigm – “synergy” – to combat infections. A case in study to reiterate this view is the observation on the combined action of berberine and 5′-methoxyhydnocarpin, both of which are produced by berberry plants. Berberine, a hydrophobic alkaloid that intercalates into DNA, is ineffective as an antibacterial because it is readily extruded by pathogen – encoded multidrug resistance pumps (MDRs). Hence, the plant produces 5′-methoxyhydnocarpin that blocks the MDR pump (Stermitz et al., 2000). This combination is a potent antibacterial agent (Lewis and Ausubel, 2006). Using this cue, Ball et al. (2006) reported that covalently linking berberine to INF55, an inhibitor of MDR, results in a highly effective antibiotic that readily accumulates in bacteria.

This paper introduces and provides examples of synergistic interactions of the secondary metabolites of plants with antibiotics in the treatment of infectious diseases. The understanding of the molecular mechanisms of synergy would pave a new strategy for the treatment of infectious diseases, overcome drug-resistant pathogens, and decrease the use of antibiotics and hence the side effects created by them.

Section snippets

Synergy towards bacterial infection

The development of antibiotic resistance can be natural (intrinsic) or acquired and this can be transmitted within same or different species of bacteria. Natural resistance is achieved by spontaneous gene mutation and the acquired resistance is through the transfer of DNA fragments like transposons from one bacterium to another. Bacteria gains antibiotic resistance due to three reasons namely: (i) modification of active site of the target resulting in reduction in the efficiency of binding of

Receptor or active site modification

For selective antimicrobial action the target site plays a vital role. Introduction of mutations in the target site alters it, leading to a reduction in the activity of the drug towards the microbe. Two examples of receptor (target) modification are (a) mutations in RNA polymerase and DNA gyrase, rendering rifamycins and quinolones inactive (Heep et al., 2000; Willmott and Maxwell, 1993), and (b) modification in the structural confirmation of penicillin-binding proteins (PBPs) resulting in the

Enzymatic degradation and modification of the drug

Bacterial cells spend a considerable amount of energy to resist antibiotics. One way the cells achieve active drug resistance is by the synthesis of enzymes that selectively target and destroy or modify the antibiotics. The various enzymatic strategies that lead to antibiotic inactivation are through hydrolysis, group transfer or redox mechanisms (Wright, 2005). Hydrolytically susceptible chemical bonds (such as ester or amide bonds) are cleaved by enzymes that are expressed by the resistant

Reduced accumulation of the antibiotic within the bacterial cell

Reduced accumulation of the antibiotic inside the microorganism could be because of two reasons namely decreased permeability of the drug through the outer membrane of the cell or, the efflux of the accumulated drug out of the cell.

Synergy and MDRTB therapy

Tuberculosis has established itself as a primary health threat. Few new agents are in development today for treating TB, and none has been designed specifically to shorten the treatment regimen and provide the breakthrough in therapy that is sorely needed if the epidemic is to be brought under control. Drug design targeting the latency stage and synergistic interaction between the various drug candidates might prove to be good alternatives.

Antimycobacterial treatment has always been a

Antifungal agents and synergism

Fungi have higher number of chromosomes and complex nuclear membrane, cell organelles and cell wall composition. Since the last three decades, the rate of death every year due to fungal infections has risen significantly. With the increased use of antifungal agents there is an increase in the number and variety of fungal strains resistant to these drugs. Also the present antifungal therapeutics is often toxic. Alternative therapy needs to be developed to suppress the emergence of antifungal

In vitro evaluation of synergy

The accurate prediction of synergy between commercial drugs or between a drug and a natural product based upon the results of in vitro testing is very crucial. A number of methods are used to detect synergy. However, the checkerboard and time-kill curve methods are the two most widely used techniques and the former is a relatively easy test to perform (White et al., 1996). The checkerboard is prepared in microtiter plate for multiple combinations of two antimicrobial agents in concentrations

Analysis of the synergy data

In all the above methods the interaction between the two antimicrobial agents is estimated by calculating the fractional inhibitory concentration of the combination (FIC) index. The FIC of each drug is calculated by dividing the concentration of the compound present in that well in combination where complete inhibition of growth of the microorganism is observed by the MIC of that compound alone to inhibit the microorganism. The FIC of the combination is then the sum of these two individual FIC

Synergistic interactions in other therapies

The successful use of combinations of plant extracts is not only observed in antiinfective therapy, but also seen in the treatment of several disorders including cancer, HIV, inflammatory, stress-induced insomnia, osteoarthritis and hypertension (Williamson, 2001). Conventional medicine applies the “silver bullet” method, where single target therapy is employed. The recent trend has been the “herbal shotgun” method like Ayurveda, where multitargeted approach of the herbals and drugs is used.

Conclusions

Before prescribing an antibiotic treatment the guidelines usually suggest that a specimen containing the suspected organism is sent for culture and sensitivity. Microbiology departments, for their part, use in vitro sensitivity of isolates taken from patients with bacterial infections to recommend which antibiotic(s) to prescribe or to use as an empirical guide for treatment in other situations. There are a number of reports available on the different antibiotic combinations tested in vitro and

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