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Applied and Environmental Microbiology, September 2006, p. 5790-5793, Vol. 72, No. 9
0099-2240/06/$08.00+0     doi:10.1128/AEM.03032-05

Transformation of the Antibacterial Agent Norfloxacin by Environmental Mycobacteria

Michael D. Adjei,1,{dagger} Thomas M. Heinze,2 Joanna Deck,1 James P. Freeman,2 Anna J. Williams,1 and John B. Sutherland1*

Divisions of Microbiology,1 Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas2

Received 23 December 2005/ Accepted 18 June 2006


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Because fluoroquinolone antimicrobial agents may be released into the environment, the potential for environmental bacteria to biotransform these drugs was investigated. Eight Mycobacterium sp. cultures in a sorbitol-yeast extract medium were dosed with 100 µg ml–1 of norfloxacin and incubated for 7 days. The MICs of norfloxacin for these strains, tested by an agar dilution method, were 1.6 to 25 µg ml–1. Cultures were extracted with ethyl acetate, and potential metabolites in the extracts were purified by high-performance liquid chromatography. The metabolites were identified using mass spectrometry and nuclear magnetic resonance spectroscopy. N-Acetylnorfloxacin (5 to 50% of the total absorbance at 280 nm) was produced by the eight Mycobacterium strains. N-Nitrosonorfloxacin (5 to 30% of the total absorbance) was also produced by Mycobacterium sp. strain PYR100 and Mycobacterium gilvum PYR-GCK. The MICs of N-nitrosonorfloxacin and N-acetylnorfloxacin were 2- to 38- and 4- to 1,000-fold higher, respectively, than those of norfloxacin for several different bacteria, including the two strains that produced both metabolites. Although N-nitrosonorfloxacin had less antibacterial activity, nitrosamines are potentially carcinogenic. The biotransformation of fluoroquinolones by mycobacteria may serve as a resistance mechanism.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Environmental residues of fluoroquinolone antibacterial agents, such as ciprofloxacin and norfloxacin (11), are of concern because they may select for resistant strains of potentially pathogenic bacteria (12). Because fluoroquinolones are excreted largely unchanged (30), they may be released into the environment (28). Several fluoroquinolones are metabolized by soil fungi, but the role of bacteria in fluoroquinolone metabolism has been less studied (8, 25, 37).

Norfloxacin is a fluoroquinolone used in the treatment of several bacterial diseases, including urinary tract infections in humans (17), enteritis in dogs (2), and chronic respiratory disease in chickens (34). A dextran-linked prodrug has been developed from norfloxacin for treatment of Mycobacterium bovis infections (10). Metabolism of norfloxacin via N acetylation, oxidation, and breakdown of the piperazine ring has been reported for humans (26) and fungi (25).

Several Mycobacterium spp. biotransform fluoroquinolones, polycyclic aromatic hydrocarbons (PAHs), and other ring compounds (8, 13). Chen et al. (8) demonstrated by chromatographic techniques and radiolabeling methods that several soil microorganisms, including two strains of mycobacteria, biotransform the fluoroquinolone danofloxacin to N-desmethyldanofloxacin, 1-cyclopropyl-6-fluoro-7-amino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, and other metabolites that may also include CO2. However, nothing is known about the bacterial transformation of other fluoroquinolones that may persist in the environment (11, 28).

Based on this existing knowledge and on the potential of mycobacteria to degrade high-priority pollutants, such as PAHs (5, 9, 13), we screened extracts from dosed cultures of environmental Mycobacterium strains for fluoroquinolone degradation, using norfloxacin as a model compound. We used a medium containing D-sorbitol and yeast extract rather than the glucose, soybean meal, and yeast extract medium used by Chen et al. (8). This study reports the transformation of norfloxacin by eight of these strains.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The Mycobacterium strains (Table 1) were grown for 4 days at 30°C with shaking at 200 rpm in a phosphate-basal minimal medium (15) with 9.0 g liter–1 D-sorbitol and 0.5 g liter–1 yeast extract. Duplicate cultures were washed in 20 mM potassium phosphate buffer (pH 7.2) and resuspended in phosphate-basal minimal medium containing 2.5 g liter–1 D-sorbitol and 0.1 g liter–1 yeast extract. They were dosed with 100 µg ml–1 norfloxacin (Sigma Chemical Co.) and incubated for 7 days. Cultures without norfloxacin and noninoculated flasks containing norfloxacin were used as controls.


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  		TABLE 1. Characteristics of Mycobacterium sp. strains transforming norfloxacin

 
Cultures and controls were centrifuged at 15,000 x g for 10 min at 4°C and then extracted three times with ethyl acetate. The solvent was evaporated in vacuo, and the residues were dissolved in methanol. Metabolites were purified by high-performance liquid chromatography (HPLC) using a Hewlett-Packard 1100 series chromatograph and a modification of the method of Parshikov et al. (23); solvent B was increased from 10% to 95% over 20 min and then held at 95% for 10 min. The flow rate was 1.0 ml min–1.

Liquid chromatography/electrospray ionization-mass spectrometric (LC/ESI-MS) and -tandem mass spectrometric (LC/ESI-MS/MS) analyses were performed using a ThermoFinnigan Quantum Ultra mass spectrometer operated in the positive-ion ESI mode with a Hewlett-Packard 1100 series HPLC and a Prodigy 5-µm ODS-3 column (250 by 2.0 mm). The mobile phase, a linear gradient of 5 to 95% acetonitrile in water over 40 min with the formic acid level held constant at 0.1%, was delivered at 0.2 ml min–1. The ESI conditions included an in-source collision-induced dissociation offset of –20 V, a spray voltage of 3.0 kV, and a capillary temperature of 350°C. Full scans were acquired from m/z 100 to 550 in 1 s. For MS/MS, the collision gas was argon at 1.5 mtorr.

1H nuclear magnetic resonance (NMR) spectroscopy was performed at 500 MHz using deuterated methanol (24).

MICs were determined by an agar dilution method (14) using Mueller-Hinton (Sigma Chemical Co.) agar plates. Serial dilutions of antibacterial agents from stock solutions were prepared in agar (14). For mycobacteria, inocula were prepared from 72-h cultures diluted to a 0.5 McFarland standard, and duplicate plates (104 CFU/spot) were incubated at 30°C for 72 h. For other bacteria, inocula were prepared from 18-h cultures, and duplicate plates (104 CFU/spot) were incubated at 35°C for 18 h. The lowest concentration that inhibited visible growth was defined as the MIC.

N-Acetylnorfloxacin (22) was synthesized from 17 mg norfloxacin dissolved in 5 ml water containing 5 drops of 1 M HCl. Acetic anhydride (0.3 ml) was added and stirred briefly; small amounts of NaHCO3 were added until the effervescence ceased (3). The mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was characterized by mass spectral and NMR analyses and stored at –80°C.

N-Nitrosonorfloxacin was synthesized by the method of Sidgwick (32). To 20.7 mg NaNO2 dissolved in water, 0.3 ml of 1 M HCl was added slowly until the pH was acidic. The mixture was sparged with argon for 1.0 min; 17 mg norfloxacin was then added and stirred overnight. The mixture was extracted, and the resultant yellow material was analyzed and stored as described above.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The MICs of norfloxacin for the Mycobacterium sp. strains were 1.6 to 25.0 µg ml–1 (Table 1); the least susceptible strains were Mycobacterium sp. strain PYR100 and Mycobacterium sp. strain 7E1B1W. Eight strains transformed norfloxacin to one or two metabolites (Table 1), neither of which was found in the controls.

Metabolite 1 eluted at 18.7 min from the HPLC column (Fig. 1A); the largest concentration (50% of the integrated A280 peak area) was produced by Mycobacterium sp. strain 7E1B1W. The mass spectra (LC/ESI-MS and -MS/MS) for metabolite 1 and synthetic N-acetylnorfloxacin show identical protonated molecules (m/z 362) and product-ion spectra (Fig. 2A). Electron ionization mass spectra and UV spectra (not shown) were also in agreement. The NMR spectrum (Table 2) showed all of the proton resonances of norfloxacin plus a singlet at 2.16 ppm (25). Nuclear Overhauser effect experiments showed that the singlet was associated with an acetyl group attached to the distal nitrogen of the piperazine ring. By comparing the UV, mass, and NMR spectra with those for the synthetic compound, metabolite 1 was determined to be N-acetylnorfloxacin (Fig. 3).


Figure 1
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  		FIG. 1. HPLC elution profiles of ethyl acetate extracts from Mycobacterium sp. strain 7E1B1W (A), M. gilvum PYR-GCK (B), and Mycobacterium sp. strain PYR100 (C), all dosed with norfloxacin (NFX). M1 and M2, metabolites 1 and 2.

 

Figure 2
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  		FIG. 2. Product-ion mass spectra of norfloxacin metabolites with argon collision gas at 1.5 mtorr. (A) Metabolite 1 from Mycobacterium sp. strain 7E1B1W. The parent ion m/z is 362, and the collision energy is 35 eV. (B) Metabolite 2 from M. gilvum PYR-GCK. The parent ion m/z is 349, and the collision energy is 25 eV.

 

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  		TABLE 2. 1H NMR chemical shifts and coupling constantsa for norfloxacin metabolites produced by Mycobacterium strains

 

Figure 3
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  		FIG. 3. Norfloxacin (with positions numbered) and the metabolites produced by Mycobacterium spp. R stands for H in norfloxacin, COCH3 in N-acetylnorfloxacin, and NO in N-nitrosonorfloxacin.

 
The HPLC chromatograms of two of the strains contained not only metabolite 1 at 18.7 min but also metabolite 2 at 19.0 min (Fig. 1B and C). For Mycobacterium gilvum PYR-GCK, peak M1 was 20% of the total integrated A280 peak area and peak M2 was 5%, and for Mycobacterium sp. strain PYR100, peak M1 was 5% and peak M2 was 30%. The mass spectra (LC/ESI-MS and -MS/MS) for metabolite 2 and synthetic N-nitrosonorfloxacin show identical protonated molecules (m/z 349) and product-ion spectra (Fig. 2B). Electron ionization mass spectra and UV spectra (not shown) were also in agreement. The NMR spectrum (Table 2) showed most of the same chemical shifts as norfloxacin but suggested that the 29-Da addition indicated by mass spectrometry was on the piperazine ring. By comparing the UV, mass, and NMR spectra with those for the synthetic compound, metabolite 2 was determined to be N-nitrosonorfloxacin (Fig. 3).

To compare the MICs of the metabolites with that of norfloxacin for different bacteria, N-nitrosonorfloxacin produced by Mycobacterium sp. strain PYR100 and synthetic N-acetylnorfloxacin were used for one experiment. The activities of both compounds against the gram-positive and gram-negative bacteria tested were much lower than those of norfloxacin (Table 3). Escherichia coli showed the highest susceptibility to norfloxacin and N-nitrosonorfloxacin. Mycobacterium gilvum PYR-GCK and Mycobacterium sp. strain PYR100, the two strains that produced both metabolites, were less susceptible to either metabolite than to norfloxacin.


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  		TABLE 3. In vitro activities of norfloxacin, N-acetylnorfloxacin, and N-nitrosonorfloxacin against selected clinical and environmental strains

 

   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Two environmental Mycobacterium strains (Mycobacterium sp. strain 7E1B1W and Mycobacterium sp. strain PYR100) and Mycobacterium smegmatis mc2155 were less susceptible to norfloxacin than most of the clinical isolates tested by Texier-Maugein et al. (36). Because norfloxacin enters mycobacterial cells quickly by simple diffusion (38), the abilities of these strains to transform norfloxacin may partly explain their resistance. Mutations in DNA gyrase genes (35) and possession of multidrug efflux pumps (18) may also contribute.

Eight Mycobacterium strains produced N-acetylnorfloxacin; this and other acetylated metabolites have been identified in cultures of some fungi dosed with fluoroquinolones (24, 25). N acetylation inactivates many antimicrobial agents, such as chloramphenicol and aminoglycosides (40), and the inactivation of isoniazid by some mycobacteria is attributed to N acetylation (27). Although N-acetylnorfloxacin has been found in human urine (26), we have not seen any published data on the MIC of N-acetylnorfloxacin for bacteria. However, Robicsek et al. (29) have reported recently that the MIC of N-acetylciprofloxacin for Escherichia coli is four times that of ciprofloxacin.

Bacterial nitrosation of secondary amines is common in the environment (1), but mycobacteria have not been shown previously to perform this reaction. The nitrosation of morpholine with nitrite at pH 7.2 is attributed to nitrate reductase or cytochrome cd1-nitrite reductase (6, 7). The nitrosation of piperazine rings can be accomplished with either nitrate or nitrite by some bacteria from human saliva (41). M. gilvum PYR-GCK and Mycobacterium sp. strain PYR100, the strains that produced N-nitrosonorfloxacin, are PAH-degrading strains isolated from river sediment and humus, respectively (9, 15, 16). The medium we used had 500 mg of NaNO3 liter–1, a concentration greater than the typical amounts of nitrate found in soil or water (21). Our results may be relevant to high-nitrate environments, such as heavily fertilized agricultural soils.

N-Nitrosonorfloxacin had a higher MIC than norfloxacin against all the bacteria in this study, although it was still moderately effective against E. coli. The results indicate that N nitrosation may serve as a mechanism to decrease the antibacterial properties of norfloxacin. Although 1-nitroso-4-methylpiperazine is not carcinogenic to rats (20), most nitrosamines are known to be carcinogenic (19), and the carcinogenicity of N-nitrosonorfloxacin is unknown.

In conclusion, norfloxacin was transformed by several Mycobacterium sp. strains via N acetylation and in some strains also via N nitrosation. The types of fluoroquinolone metabolites produced in these experiments were different from those reported previously by Chen et al. (8). Biotransformation reduced the antibacterial activity of norfloxacin and therefore may serve as a mechanism facilitating fluoroquinolone resistance.


   ACKNOWLEDGMENTS
 
We thank C. E. Cerniglia for providing Mycobacterium strains and for helpful suggestions and comments. We also thank R. Nayak for providing other bacterial strains and F. Rafii and D. D. Paine for advice on testing antibacterial activity.

This work was supported in part by an appointment (M.D.A.) to the Postgraduate Research Fellowship Program at the National Center for Toxicological Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

The views presented in this article do not necessarily reflect those of the Food and Drug Administration.


   FOOTNOTES
 
* Corresponding author. Mailing address: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079. Phone: (870) 543-7059. Fax: (870) 543-7307. E-mail: john.sutherland{at}fda.hhs.gov. Back

{dagger} Present address: Norfolk Department of Public Health, 830 Southampton Ave., Norfolk, VA 23510. Back


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Applied and Environmental Microbiology, September 2006, p. 5790-5793, Vol. 72, No. 9
0099-2240/06/$08.00+0     doi:10.1128/AEM.03032-05




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