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fungal infections , both community acquired and nosocomial represent a major challenge , particularly in immunocompromised patients , as the organisms tend to be resistant to common drugs .
amphotericin b ( amb ) , a potent polyene is one of the drugs used in therapy for patients with deep - seated fungal infections caused by acquired immunodeficiencies and transplantations.1 though it remains a potent antifungal drug , its use is hampered by its low solubility in water and toxic side effects.2 to circumvent these side effects , various drug formulations such as liposomes , deoxycholate salts , and nanospheres have been reported and used for treatment.2 some of these formulations are less toxic than others , but each has its own limitations . to circumvent these limitations , the interaction of amb with serum albumins has been studied by a few groups , notably by butler et al and romanini et al.3,4 serum albumins are known for their ability to bind a variety of ligands .
this property helps to render a water - insoluble substance soluble and transportable.6 their lack of immunogenicity and toxicity coupled with abundant availability makes them ideal candidates for drug delivery .
human serum albumin ( hsa ) is used as an excipient in some drugs and is also used for treating shock , burns , and acute respiratory distress , and in hemodialysis.5,6 bovine serum albumin ( bsa ) was also investigated as it is structurally homologous to hsa.7 considering the significant advantages of serum albumin as a drug delivery system , we resorted to in - silico analysis to identify the putative binding regions of amb to serum albumin .
earlier reports by romanini et al suggest that in hsa the residues lysine 199 and 525 participate in amb 
hsa interaction with binding energies around 10 m.4 for our analysis , autodock 3.0 suite developed by scripps research institute was used to compute and determine the region of amb binding on serum albumins.8 our docking results indicate that both human and bovine serum albumins have only one favorable binding site each for amb .
amb binds to hsa away from the central cleft of the molecule and interacts with six amino acids ( at 3 vicinity ) in domain iiia .
these include , two glu ( 392 , 396 ) and two gln ( 518 , 400 ) residues and one residue each of arg424 and ser431 ( figure 1 ) . on bsa ,
amb binds in the cleft region , interacting with seven amino acids , of which two are lys ( 138 , 455 ) and one residue each of asp135 , glu423 , gln427 , arg451 , thr542 ( figure 2 ) .
the spectra of both bsa and hsa complexed with amb had some characteristic perturbations especially at around 335340 nm ( figures 3a and 4a ) .
amb in phosphate - buffered saline with 1% dimethyl sulfoxide ( dmso ) displayed a characteristic peak at 340 nm , while the complex showed a spectral blue - shift of about 5 nm .
in addition , a hyperchromic peak was observed , which may be attributed to the change in the environment of the molecule .
the increasing absorbance at 335 nm is similar to the changes of the amb spectrum displayed in the aggregated state in water .
romanini et al observed and postulated that this hyperchromicity is due to the  self perturbation  of the amb dipole during dimer formation and is caused by dipolar forces involving polar groups present in the amb molecule.4 such prior observations agree with the notion that the amb monomer interacts with the polar groups present on the bound serum albumin .
the antifungal activities of the amb  albumin ( hsa and bsa ) complexes were tested by broth dilution against candida albicans and c. glabrata .
results from these experiments suggest that the complex retains antifungal activity that is equivalent to the drug alone ( table 1 ) . since amb
is known to cause lysis of erythrocytes , the complexes were also tested for hemolytic activity on human erythrocytes.9 the results showed that the prepared complexes have only a marginal protective effect against membrane damage ( figure 6 , samples e and f ) .
several published reports show that amb has a permeabilizing effect on red blood cell membrane.9 brajtburg et al have reported that the auto - oxidation of the polyene drug releasing reactive oxygen species leads to these anticellular effects.10 hence , we thought that the addition of a free radical scavenger or an antioxidant in the above albumin  amb complex would help to lessen the hemolytic activity of the drug .
curcumin , a yellow pigment isolated from the rhizomes of curcuma longa has been reported to possess antioxidant activity and known to exhibit various pharmacological effects including antimicrobial and anticancer properties.11 coincidently , curcumin too is insoluble in aqueous medium and is poorly absorbed by the body.12 various formulations like polymeric nanoparticles and liposomes have been prepared to increase the bioavailability.13,14 incidentally , tsao et al reported that the presence of curcumin enhanced the inhibitory activity of amb against candida spp.15 this report , combined with the known antioxidant property , prompted us to investigate the use of curcumin along with amb .
barik et al have reported the formation of bsa  curcumin complex with binding constants in the order of 1010 m.16 the same group has also studied the formation of hsa  curcumin complex and reported that the site of curcumin binding to hsa is likely to be at domain iia , with binding constant estimated to be around 7.9  10 m.17 the latest report from bourassa et al on curcumin binding to bsa indicate the number of bound polyphenols ( n ) to be 1.0 and the binding constant to be 3.33 ( 0.8 )  10 m.7 the docking simulations carried out by us indicate the presence of a single binding site on hsa , located away from the trp214 , on domain ib ( figure 1 ) .
with bsa , curcumin is more likely to bind in the vicinity of trp158 ( figure 2 ) .
the proposed complex of curcumin with hsa / bsa was prepared , and spectral properties determined ( figure 5 ) .
albumin complex showed no intrinsic antifungal activity ( data not shown ) and was found to be nonhemolytic in nature ( figure 6 , sample b ) .
since the binding site of curcumin was located in a different domain of albumins ( figures 2 and 3 ) , there was a distinct possibility of formation of ternary complex involving albumins , amb , and curcumin .
we therefore prepared an albumin , amb , and curcumin complex . the prepared complex was water soluble ( 10 mg of protein / ml of water ) .
the spectral properties indicate the presence of hyperchromic peak at 335 nm similar to amb  albumin complex with a broad shoulder around 450 nm representative of curcumin .
testing of a mixture of free amb and curcumin in the in vitro red cell lysis assay shows that the lysis induced by the antifungal agent is delayed ( figure 6 , sample d ) .
when both the components are protein bound , the process of lysis is delayed even more ( figure 6 , samples g and h ) .
significantly , however , this reduction of hemolysis was achieved without compromising the antifungal activity of the ternary complex and was seen to be equivalent to that of albumin  amb complex and the drug alone ( table 1 ) .
since the binding site of curcumin was located in a different domain of albumins ( figures 2 and 3 ) , there was a distinct possibility of formation of ternary complex involving albumins , amb , and curcumin .
we therefore prepared an albumin , amb , and curcumin complex . the prepared complex was water soluble ( 10 mg of protein / ml of water ) .
the spectral properties indicate the presence of hyperchromic peak at 335 nm similar to amb  albumin complex with a broad shoulder around 450 nm representative of curcumin .
testing of a mixture of free amb and curcumin in the in vitro red cell lysis assay shows that the lysis induced by the antifungal agent is delayed ( figure 6 , sample d ) .
when both the components are protein bound , the process of lysis is delayed even more ( figure 6 , samples g and h ) .
significantly , however , this reduction of hemolysis was achieved without compromising the antifungal activity of the ternary complex and was seen to be equivalent to that of albumin  amb complex and the drug alone ( table 1 ) .
there are several reports on the interaction of amb with albumin , and curcumin with albumin .
these studies have focused more on understanding the nature of interaction between albumin and the ligand . even though there are a few reports on the amelioration of toxic effects of certain drugs by curcumin , the use of the drug alone with curcumin in a protein - complexed form and its beneficial biological effects have not been reported .
this indicates that the translocation of the antifungal agent from the protein to target membrane occurs readily .
although two distinct sites were noted for amb and curcumin in the in silico study , there is no unequivocal evidence to show that the albumin  drug complex used in the present study is loaded with both ligands on all the protein molecules .
it is quite likely that the complex preparation consists of a mixture of albumin molecules , some carrying both ligands , some with one ligand , and some free protein molecules .
the presence of curcumin in proximity to amb may not have much significance in so far as the biological effect is concerned .
what is perhaps important is the availability of curcumin at the site of action of amb
. it may be relevant to mention here that ali et al reported the amelioration of the nephrotoxic effect of gentamicin by curcumin in rats.18 in this case , gentamicin was administered intramuscularly , while curcumin was given orally .
there is also a report of enhancement of antifungal activity of amb or fluconazole towards candida species by curcumin .
cucumin has been shown to have protective effect on primaquine - induced oxidative damage.19 amb is thought to damage the mammalian cell membrane by formation of channels traversing membranes , and this requires self - associated molecules.2 whatever the mechanism of the damage process , we have also observed that with free amb and curcumin together , the red cell lysis process is delayed .
kala - azar ( visceral leishmaniasis ) disease caused by protozoal parasite leishmania donovani responds to treatment with amb . in the light of the finding
reported here , it may be worthwhile to investigate the therapeutic use of a combination of amb and curcumin in the protein bound form .
amphotericin and curcumin are known to form complexes with albumins individually . 
 in - silico analysis shows that amphotericin b and curcumin have separate binding regions on human serum albumin and bovine serum albumin . 
 the complex formed with albumin in the presence of both amphotericin and curcumin is water soluble , and it retains antifungal activity . 
 interestingly , it was found that the presence of curcumin in the complex significantly delayed the red cell lysis by amphotericin b , indicating the possibility of moderating the toxic side effects of the drug using curcumin . 
 furthermore , since the presumed ternary complex is stable and water soluble , its potential use in the treatment of visceral leishmaniasis ( kala azar ) and systemic fungal infections needs to be evaluated .