Curcumin, Bacteria and Antibiotics

This page is about Curcumin and bacteria. How Curcumin may reduce bacterial growth, inhibit biofilm formation and inhibit quorum sensing (explanations included) and about how Curcumin seems to work together with antibiotics.
I have been asked a few times about possible interactions (or interference) between Curcumin & Genistein and antibiotics. After searching PubMed I noticed there are more articles available about the synergy between Curcumin and antibiotics, than there are about possible interactions. Note that synergy means that they work better together, without interacting (raising blood serum levels, side effects or time for the body to fully break down the antibiotic (t1/2)). 

 The one thing that possibly causes interactions is the Piperine (black pepper extract) added to many Curcumin formulations. I'll continue this page at a later date with information about possible interactions between Piperine and antibiotics. For now I can only say that Piperine inhibits Cyp3a4, but I'm not sure about amounts (how many mg's of Piperine) and how strongly it inhibits. If in doubt, ask your pharmacist about it. Or, as I mention on another page, if you take oral antibiotics often, it may be a better idea to use a Phytosome Curcumin as it doesn't contain Piperine and is absorbed just as well because of the Phytosome form.

 In the human body it is unlikely that it is possible to reach the Curcumin concentrations used in the studies below, by taking oral supplements.  But the idea is clear and I'm assuming (hoping) any little bit of Curcumin will help antibiotics work better. 
(note to self: 10µM equals 3.7µg/mL)
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Curcumin with Cefaclor, Cefodizime and Cefotaxime against a.o. Staph Aureus, Pseudomonas Aeruginosa and E. Coli.
(This particular article was actually about diarrhea causing bacteria, but it gives you an idea of how Curcumin works synergistically with antibiotics)

Comment: Okay, look at the columns 'Alone' and 'Combination' in the table below. 
For example the first value CUR-1 Alone: 250/500. 
That means if you add Curcumin alone to S. Aureus, the minimal concentration (amount) of Curcumin needed to stop S. Aureus from growing (inhibit growth) is 250(µg/mL). 
That's the MIC: Minimal Inhibitory Concentration. 
The second number: 500, is the minimal concentration of Curcumin needed to kill all bacteria. 
That's the MBC: Minimal Bactericidal Concentration.

Now look at Cefaclor Alone and then at Combination. See how Cefaclor's MBC (bactericidal concentration) was 16 and together with Curcumin it goes down to 2? That means without Curcumin you need 16 µg/mL, but in combination with Curcumin you only need 2µg/mL to kill all bacteria. So just take less antibiotics? There is a another way to look at it, see graph below.



Now look at it from another view point. Here, for example, is the Time-kill curve for Pseudomonas:



The bottom 3 lines are antibiotics + Curcumin. Combined they reduce the number of PA bacteria to zero faster! Very good! This happened for all bacteria tested, by the way. 

Below are some pieces of the article:

"All of the organisms examined exhibited a 3- to 8-fold reduction in MIC values with CUR-1 and the three antibiotics. Curcumin has been reported having an extremely good safety profile and no toxicity observed when taken at doses as high as 12 g/day in in vivo test. In our study also curcumin recorded no toxicity up to 200 μg/mL."
"In this study we looked at the effects of combining the curcumin with three antibiotics against bacteria. In the present study curcumin alone recorded antimicrobial activity at higher concentration. This is in accordance with the previous report. But curcumin in combination with antibiotics recorded significant synergistic effect. When used together, the drugs were not only synergistic but also bactericidal and prevented the regrowth of bacteria in time-kill assays. These data suggest that curcumin in combination with antibiotics could be a useful option for the treatment of complicated bacterial infections. In addition to achieving these synergistic effects, the combinations of two or more compounds are essential for the following reasons: (1) to prevent or suppress the emergence of resistant strains, (2) to decrease dose-related toxicity, as a result dosage, and (3) to attain a broad spectrum of activity."
"Bacteria develop resistance to antibiotics and this is associated with an increase in the MIC of one or more antibiotics. This means that when a patient has a clinical disease that is caused by a resistant bacterium, treatment with the antibiotic to which the bacterium is resistant is less effective. Sometimes, it is possible to simply increase the dose of the antibiotic to overcome the bacterial resistance. However, for many antibiotics, such as aminoglycosides, it is not feasible to significantly increase the dose of the antibiotic because of toxic side effects. In these circumstances, benefit for the patient could be achieved by enhancing the effect of the antibiotic against resistant bacteria. Here, we clearly showed that curcumin enhances the activity of cefaclor, cefodizime, and cefotaxime. Most interestingly, the bactericidal activities of the tested drugs were significantly enhanced. Synergistic effect of curcumin with antibiotics is previously reported against methicillin-resistant Staphylococcus aureus and Candida albicans. Synergistic effect of curcumin and antibiotics against bacteria associated with diarrhea is reported here for the first time."

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Phytomedicine. 2013 Jun 15;20(8-9):714-8. doi: 10.1016/j.phymed.2013.02.006. Epub 2013 Mar 26.

Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus.

Mun SH1, Joung DK, Kim YS, Kang OH, Kim SB, Seo YS, Kim YC, Lee DS, Shin DW, Kweon KT, Kwon DY.

The MICs of CCM against 10 strains of S. aureus ranged from 125 to 250 μg/ml. In the checkerboard test, CCM markedly reduced the MICs of the antibiotics oxacillin (OXI), ampicillin (AMP), ciprofloxacin (CIP), and norfloxacin (NOR) used against MRSA. The time-kill curves showed that a combined CCM and OXI treatment reduced the bacterial counts below the lowest detectable limit after 24h. This study suggested that CCM reduced the MICs of several antibiotics tested, notably of OXI, AMP, CIP, and NOR, and that CCM in combination with antibiotics could lead to the development of new combination of antibiotics against MRSA infection.

Comment: The article above says that CCM (=Curcumin) was tested against 10 different strains of Methicillin Resistant Staphylococcus Aureus. The effect depended on the strains used, but all MIC's (Minimal Inhibitory Concentration, so minimal amount needed to stop growth of bacteria) of antibiotics tested were reduced when Curcumin was added. Very good!

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Mikrobiyol Bul. 2013 Jan;47(1):192-4.

[Effects of Imipenem, Tobramycin and Curcumin on Biofilm Formation of Pseudomonas aeruginosa Strains].

[Article in Turkish]
Karaman M1, Fırıncı F, Arıkan Ayyıldız Z, Bahar IH.

Abstract

Aminoglycoside antibiotics and imipenem are reported to stimulate exopolysaccharide alginate production and cause an increased biofilm volume in Pseudomonas aeruginosa. Recently, some remarkable studies have been conducted on the effects of curcumin (Turmeric), which is the fenolic form of Curcuma longa plant, on virulence factors of P.aeruginosa. In this study, we aimed to investigate the effects of MIC and sub-MIC concentrations of imipenem, tobramycin, and curcumin on biofilm formation of P.aeruginosa strains. P.aeruginosa strains (n= 2) used in this study were isolated from deep oropharyngeal swab samples of two cystic fibrosis patients. Antimicrobial susceptibilities of the two strains to imipenem, tobramycin, and curcumin were investigated by broth microdilution method, and biofilm production was assessed by using crystal violet staining method. In our study, MIC values of imipenem, tobramycin and curcumin for strain-1 were 8 µg/ml, 8 µg/ml and 16 µg/ml, respectively, while those values were 4 µg/ml, 8 µg/ml and 16 µg/ml for strain-2. Biofilm optical density values of the strain-1 and strain-2 before being treated with the test substances were 0.937 and 0.313 (control: 0.090), respectively, Biofilm optical densities of the both strains showed an increase following treatment with MIC concentrations of imipenem and tobramycin. The treatment of the strains with MIC and sub-MIC concentrations of curcumin led to no significant increase in biofilm optical density. The data obtained in this study supported the promising inhibitory effect of curcumin on P.aeruginosa biofilms. However, further more comprehensive studies are required to provide satisfactory data about the use of curcumin to treat P. Aeruginosa infections characterized by biofilm formation.


Comment: A biofilm is an alginate layer that Pseudomonas bacteria create around a colony to protect itself. This is what differentiates 'mucoid Pseudomonas' from 'non-mucoid Pseudomonas'. The 'mucoid' means that the bacteria have formed a biofilm. It makes it a lot more difficult to eradicate from the CF airways.
I have to admit, I don't really understand what they are trying to explain in the abstract and I don't have acces to the full article (nor do I understand Turkish) to find out what they mean exactly. I'm relying on their conclusion that they have found reason to assume that Curcumin has an inhibitory effect on biofilm formation of Pseudomonas Aeruginosa, which, again, is really good.

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Food Chem. 2014 Apr 1;148:453-60. doi: 10.1016/j.foodchem.2012.08.002. Epub 2012 Aug 10.

Inhibition of biofilm development of uropathogens by curcumin - an anti-quorum sensing agent from Curcuma longa.

Packiavathy IA, Priya S, Pandian SK, Ravi AV.

Abstract

Urinary tract infection is caused primarily by the quorum sensing (QS)-dependent biofilm forming ability of uropathogens. In the present investigation, an anti-quorum sensing (anti-QS) agent curcumin from Curcuma longa (turmeric) was shown to inhibit the biofilm formation of uropathogens, such as Escherichia coli, Pseudomonas aeruginosa PAO1, Proteus mirabilis and Serratia marcescens, possibly by interfering with their QS systems. The antibiofilm potential of curcumin on uropathogens as well as its efficacy in disturbing the mature biofilms was examined under light microscope and confocal laser scanning microscope. The treatment with curcumin was also found to attenuate the QS-dependent factors, such as exopolysaccharide production, alginate production, swimming and swarming motility of uropathogens. Furthermore, it was documented that curcumin enhanced the susceptibility of a marker strain and uropathogens to conventional antibiotics.

Comment: Having explained what a biofilm is above, the next explanation, and the step preceeding biofilm formation, is Quorum Sensing (QS). QS is when bacteria in a colony communicate with each other. They 'know' when they have enough bacteria in the colony to survive and they start forming a biofilm, to protect the colony. If you can stop the bacteria from communicating (inhibit QS), the chance that they will form a biofilm is reduced. This study showed that Curcumin inhibits Quorum Sensing. It also showed that other factors involved in Quorum Sensing were attenuated. On top of that they found that Curcumin enhanced the susceptibility of bacteria to antibiotics (the antibiotics worked better, possibly due to synergistic effect of combined Curcumin and antibiotics mentioned in the other articles)

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J Agric Food Chem. 2008 Mar 26;56(6):1955-62. doi: 10.1021/jf072591j. Epub 2008 Feb 20.

Curcumin, a known phenolic from Curcuma longa, attenuates the virulence of Pseudomonas aeruginosa PAO1 in whole plant and animal pathogenicity models.

Rudrappa T, Bais HP

Abstract

The effect of curcumin on the virulence of Pseudomonas aeruginosa (PAO1) using whole plant and animal pathogenicity models was investigated. The effect of curcumin on PAO1 virulence was studied by employing in vitro assays for virulence factor production, Arabidopsis thaliana/Caenorhabditis elegans pathogenicity models, and whole genome microarray analysis. It is shown that the curcumin inhibits PAO1 virulence factors such as biofilm formation, pyocyanin biosynthesis, elastase/protease activity, and acyl homoserine lactone (HSL) production. As a consequence of this, curcumin treatment resulted in the reduced pathogenicity of P. aeruginosa-C. elegans and P. aeruginosa-A. thaliana infection models. In addition, transcriptome analysis ofcurcumin-treated PAO1 revealed down-regulation of 31 quorum sensing (QS) genes, of which many have already been reported for virulence. The supplementation of HSLs along with the curcumin treatment resulted in increased pathogencity and recovery of higher bacterial titers in a plant pathogenecity model. These data reveal the involvement of curcumin in QS interruption to reduce pathogenicity. Curcumin attenuates PAO1 virulence by down-regulation of virulence factors, QS, and biofilm initiation genes. The effect of curcumin on multiple targets such as virulence, QS, and biofilm initiation makes curcumin a potential supplemental molecule for the treatment of P. aeruginosa infections.

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J Med Microbiol. 2010 Apr;59(Pt 4):429-37. doi: 10.1099/jmm.0.016873-0. Epub 2010 Jan 7.

Curcumin alone and in combination with augmentin protects against pulmonary inflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice.

Bansal S, Chhibber S.

Abstract

Acute lung injuries due to acute lung infections remain a major cause of mortality. Thus a combination of an antibiotic and a compound with immunomodulatory and anti-inflammatory activities can help to overcome acute lung infection-induced injuries. Curcumin derived from the rhizome of turmeric has been used for decades and it exhibits anti-inflammatory, anti-carcinogenic, immunomodulatory properties by downregulation of various inflammatory mediators. Keeping these properties in mind, we investigated the anti-inflammatory properties of curcumin in a mouse model of acute inflammation by introducing   B5055 into BALB/c mice via the intranasal route. Intranasal instillation of bacteria in this mouse model of acute pneumonia-induced inflammation resulted in a significant increase in neutrophil infiltration in the lungs along with increased production of various inflammatory mediators [i.e. malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), tumour necrosis factor (TNF)-alpha] in the lung tissue. The animals that received curcumin alone orally or in combination with augmentin, 15 days prior to bacterial instillation into the lungs via the intranasal route, showed a significant (P <0.05) decrease in neutrophil influx into the lungs and a significant (P <0.05) decrease in the production of MDA, NO, MPO activity and TNF-alpha levels. Augmentin treatment alone did not decrease the MDA, MPO, NO and TNF-alpha levels significantly (P >0.05) as compared to the control group. We therefore conclude that curcumin ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly (P <0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, curcumin can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in the case of acute lung infection.

Comment: This article doesn't talk about antibiotics specifically, but gives a idea of what else Curcumin may do besides enhancing antibiotics. In mice infected with pneumonia, inflammation increased. From the article: "Most antibiotics reduce bacterial load and do not provide protection against organ damage generated becaue of an exaggerated immune response." Augmentin did nothing to reduce inflammation, however when they added oral Curcumin, many inflammatory markers decreased significantly. They suggest taking Curcumin and an antibiotic during lung infection. Curcumin will reduce the inflammation and the antibiotic will reduce bacterial load. In this particular study the combination of Curcumin and Augmentin did not show a synergistic inhibitory or bactericidal effect against Klebsiella pneumoniae.


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Link to abstract

Biochemistry. 2015 Feb 24;54(7):1558-66. doi: 10.1021/bi501318h. Epub 2015 Feb 11.

Interplay between Inhibitory Ferric and Stimulatory Curcumin Regulates Phosphorylation-Dependent Human Cystic Fibrosis Transmembrane Conductance Regulator and ΔF508 Activity.

Wang G1.

Abstract

Curcumin potentiates cystic fibrosis transmembrane conductance regulator (CFTR) activation in an ATP-independent but phosphorylation-dependent manner. The underlying molecular mechanisms are unclear. Here, HEK-293T cells cultured in an Fe(3+)-containing medium were transiently transfected with CFTR constructs, and the role of the inhibitory Fe(3+) bridge between intracellular loop 3 and the regulatory domain of CFTR in this pathway was investigated. The results showed that ethylenediaminetetraacetic acid (EDTA) stimulated phosphorylation-dependent CFTR activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe(3+)-binding interface. Furthermore, curcumin potentiation of CFTR was significantly weakened not only by Fe(3+)-insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N-ethylmaleimide or EDTA pretreatment that removes Fe(3+). More importantly, potentiation of CFTR was completely suppressed by sufficient Fe(3+). Finally, the insertion of Fe(3+)-insensitive H950R/S768R increased the curcumin-independent activity of ΔF508 but weakened its curcumin potentiation. Thus, Fe(3+) homeostasis in epithelia may play a critical role in regulating CFTR activity, and targeting Fe(3+)-chelating potentiators may direct new therapies for cystic fibrosis.

http://en.wikipedia.org/wiki/CYP3A4

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