Study of Antimicrobial Quinolones and Structure Activity Relationship of Anti-Tubercular Compounds

Abstract

Fluoroquinolones (FQs) are an important synthetic antimicrobial agents being clinically used. Currently some FQs are under investigation for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensive drug resistance (XDR-TB) and are under investigation as first-line drugs. Their main biological target in Mycobacterium tuberculosis is the DNA gyrase, a topoisomerase II encoded by gyrA and gyrB that is essential to maintain the DNA supercoil. The mutations in short regions of DNA gyrase are associated with quinolone resistance or hyper susceptibility and take place in several MDR clinical isolates of M. tuberculosis. The anti-TB property mode of action and structure activity relationship studies of the some known quinolone derivatives are studied. Furthermore, the activity of quinolones as new class of potent and selective anti-TB agents, particularly their activity against MDR-TB and XDR-TB.

Keywords

Quinolones, Anti-tubercular activity, MDR-TB, SAR analysis

Introduction

The first quinolone, nalidixic acid, was isolated as a by-product of the synthesis of chloroquine and used for the treatment of urinary tract infections (UTIs) for many years. The fluorinated-quinolones, like ciprofloxacin (CPFX), moxifloxacin (MFLX), and gatifloxacin (GFLX) have broad spectrum antimicrobial activity for the treatment of various pathogenic diseases. Relatively few side effects appear comes with the use of these fluoroquinolones (FQs). Microbial resistance may be developed. Rare and potentially fatal side effects have also resulted. Due to side effects the withdrawal from the market of temafloxacin (immune hemolytic anemia), trovafloxacin (hepatotoxicity), grepafloxacin (cardiotoxicity), and clinafloxacin (phototoxicity) [1].

Tuberculosis (TB) is one of the most common infectious diseases, with about one-third of world's population infected with Mycobacterium tuberculosis (Global Tuberculosis Control, 2011). Even more frightening is the emergence of extensively drug resistant TB (XDR-TB) reported in all regions of the world. The increased number of MDR strains, is closely associated to the growing global HIV/AIDS pandemic [2,3]. The association of TB and HIV infections is so dramatic that, nearly two-thirds of the patients diagnosed with TB are also HIV-1 positive [4] and the risk of developing TB is between 20 and 37 times greater in people living with HIV than among those who do not have HIV infection [5,6]. TB is the leading cause of death among HIV infected people; the WHO estimates that TB accounts for more than a quarter of deaths among people living with HIV worldwide [7]. Since HIV infection is a major risk factor for the development of active TB which, in turn is a cofactor in the progression of HIV infection [8].

Antibacterial Spectrum

The FQs are potent bactericidal agents against E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria. Ciprofloxacin (CPFX) is more active than norfloxacin against P. aeruginosa. The FQs also have good activity against staphylococci, but not against methicillin-resistant strains. Activity against streptococci is limited to a subset of the quinolones, including levofloxacin (LVFX), GFLX, and MFLX [9]. Several intracellular bacteria are inhibited by FQs; these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium [10]. Ciprofloxacin (CPFX), ofloxacin (OFLX), and pefloxacin have MIC₉₀values from 0.5 to 3 mg/ml for M. fortuitum, M. kansasii, and M. tuberculosis; OFLX and pefloxacin are active in leprosy [11]. Several of FQs have activity against anaerobic bacteria, like garenoxacin and gemifloxacin [12]. Resistance to quinolones may develop during therapy via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV or by active transport of the drug out of the bacteria [13]. Resistance has increased after the introduction of FQs, especially in Pseudomonas and staphylococci [14]. Increasing FQ resistance also is being observed in C. jejuni, Salmonella , N. gonorrhoeae, and S. pneumonia [15]. The FQs are concentration-dependent agents, resulting in bacterial eradication when unbound serum area- under-the-curve-to-MIC ratios exceed 25 to 30.

Mechanism of Action Quinolones

The quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV [16]. For many gram-positive bacteria (such as S. aureus), topoisomerase IV is the primary activity inhibited by the FQs. In contrast, for many gram-negative bacteria (such as E. coli ), DNA gyrase is the primary quinolone target [17]. To combat this problem, the bacterial enzyme DNA gyrase is responsible for the permanent introduction of negative supercoils into DNA. This is an ATP-dependent reaction requiring that both strands of the DNA be cut to permit passage of a segment of DNA through the break; the break then is resealed. The drugs inhibit gyrase- mediated DNA supercoiling at concentrations that correlate well with those required to inhibit bacterial growth. Mutations of the gene that encodes the A subunit polypeptide can confer resistance to these drugs [11,16]. This enzyme is the target for some antineoplastic agents. Quinolones inhibit eukaryotic type II topoisomerase only at much higher concentrations (100 to 1000 mg/ml) [18].

Bacterial resistance

Gram-positive and Gram-negative bacteria have been reported to be resistant to quinolones. The resistance appears to be the result of one of three mechanisms: alterations in the quinolone enzymatic targets (DNA gyrase), reduced outer membrane permeability or the development of efflux mechanisms. The accumulation of several bacterial mutations (DNA gyrase and bacterial permeability) has been linked with the development of very high MICs to ciprofloxacin in isolates of S. aureus, Enterobacteriaceae species and P. aeruginosa. Resistance to quinolones can also develop because of changes in bacterial permeability and the development of efflux pumps. This resistance mechanism is shared with antimicrobial agents structurally unrelated to the quinolones, such as the betalactams, tetracyclines and chloramphenicol (Chloromycetin). Cross-resistance among the quinolones is expected, but the extent to which the MIC is affected varies from agent to agent. Therefore, the bacterial susceptibility and pharmacokinetic profiles of each quinolone should be considered in determining the effectiveness of specific agents.

Therapeutic Uses

Urinary Tract Infections

Nalidixic acid is useful only for UTIs caused by susceptible microorganisms. The FQs are significantly more potent and have a much broader spectrum of antimicrobial activity. Norfloxacin is use for UITs and FQs are more effective than trimethoprim- sulfamethoxazole for the treatment of UTIs.

Prostatitis

Norfloxacin, CPFX, and OFLX are effective in the treatment of prostatitis caused by sensitive bacteria. Fluoroquinolones are effective in patients not responding to trimethoprim-sulfamethoxazole [19].

Sexually Transmitted Diseases

The quinolones are contraindicated in pregnancy. Fluoroquinolones (FQs) lack activity for , N. gonorrhoeae, C. trachomatis, and H. ducreyi. For chlamydial urethritis/cervicitis, OFLX or sparfloxacin (SPFX) is an alternative treatment with doxycycline or a single dose of azithromycin; other quinolones have not been reliably effective. A single oral dose of FQs such as OFLX or CPFX is effective treatment for sensitive strains of N. gonorrhoeae, but increasing resistance to FQs has led to ceftriaxone being the first-line agent for this infection. Pelvic inflammatory disease has been treated with OFLX combined with an antibiotic with activity against anaerobes (clindamycin or metronidazole). Chancroid (infection by H. ducreyi) can be treated with CPFX.

Gastrointestinal and Abdominal Infections

For traveler's diarrhea (frequently caused by entero-toxigenic E. coli ), the quinolones are equal to trimethoprim- sulfamethoxazole in effectiveness [20]. Norfloxacin, CPFX, and OFLX have been effective in the treatment of patients with shigellosis [21]. Norfloxacin is superior to tetracyclines in decreasing the duration of diarrhea in cholera. Ciprofloxacin (CPFX) and OFLX treatment cures most patients with enteric fever caused by S. typhi, as well as non typhoidal infections in AIDS patients. Shigellosis is treated effectively with either CPFX or azithromycin [22].

Respiratory Tract Infections

The key restriction to the use of quinolones for the treatment of community-acquired pneumonia and bronchitis had been the poor in vitro activity of CPFX, OFLX, and norfloxacin against S. pneumoniae and anaerobic bacteria. Many newer FQs, including GFLX and moxifloxacin, have excellent activity against S. pneumoniae. These newer quinolones shows comparable efficacy to β-lactam antibiotics [23]. The FQs have activity against the respiratory pathogens, like H. influenzae, Moraxella catarrhalis, S. aureus, M. pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Either a FQ (CPFX or LVFX) or azithromycin is of choice for L. pneumophila. The FQs have been very effective against both H. influenzae and M. catarrhalis from sputum. Mild to moderate activity exhibited against P. aeruginosa in patients with cystic fibrosis. The newer FQs are used as single agents for treatment of community-acquired pneumonia [11]. However, have decreasing susceptibility of S. pneumoniae to FQs [24].

Bone, Joint, and Soft Tissue Infections

The treatment of chronic osteomyelitis requires prolonged antimicrobial therapy with agents active against S. aureus and gram-negative rods. The FQs may be used appropriately in some cases [25]. Bone and joint infections may require treatment with FQs. Dosage should be reduced for patients with severely impaired renal function. Ciprofloxacin (CPFX) should not be given to children or pregnant women. Clinical cures have been as high as 75% in chronic osteomyelitis in which gram-negative rods predominated [11]. Failures have been associated with the development of resistance in S. aureus, P. aeruginosa, and Serratia marcescens. In diabetic foot infections, which are commonly caused by a mixture of bacteria including gram-negative rods, anaerobes, streptococci, and staphylococci, the FQs in combination with an agent with anti-anaerobic activity are a reasonable choice. Ciprofloxacin (CPFX) as sole therapy is effective in 50% of diabetic foot infections.

Other Infections

Ciprofloxacin (CPFX) wide usage for the prophylaxis of anthrax and also effective for the treatment of tularemia [26,27]. The FQs may be used as part of multiple-drug regimens for the treatment of MDR-TB and for the treatment of atypical mycobacterial infections as well as M. avium complex (MAC) infections in AIDS. In neutropenic cancer patients with fever, the combination of a quinolone with an aminoglycoside (AG) is comparable to β-lactam-AG combinations; quinolones are less effective when used alone. Quinolones, when used as prophylaxis in neutropenic patients, have decreased the incidence of gram-negative rod bacteremias. Ciprofloxacin (CPFX) plus amoxicillin-clavulanate has been effective

Adverse Effects

Quinolones and FQs generally are well tolerated [28]. The most common adverse reactions involve the GI tract, with 3% to 17% of patients reporting mostly mild nausea, vomiting, and abdominal discomfort. Diarrhea and antibiotic-associated colitis have been unusual. CNS side effects like mild headache and dizziness, in 0.9% to 11% of patients. Rarely, hallucinations, delirium, and seizures have occurred, predominantly in patients who also were receiving theophylline or a nonsteroidal anti-inflammatory drug (NSAIDs). Ciprofloxacin (CPFX) and pefloxacin inhibit the metabolism of theophylline, and toxicity from elevated concentrations of the methylxanthine may occur. The NSAIDs may augment displacement of g-aminobutyric acid (GABA) from its receptors by the quinolones [29]. Rashes, including photosensitivity reactions, also can occur. Achilles tendon rupture or tendinitis has occurred rarely. Renal disease, hemodialysis, and steroid use may be predisposing factors [28]. The use of FQs in children has been contraindicated for this reason. However, children with cystic fibrosis given CPFX, norfloxacin, and nalidixic acid have had few, and reversible, joint symptoms [30]. Leukopenia, eosinophilia, and mild elevations in serum transaminases occur rarely. Quinolones probably should be used only with caution in patients treated with amiodarone and quinidine, procainamide as antiarrhythmics ( Table 1).

Table 1: Approved clinical uses for selected fluoroquinolones.

Quinolones and Chemotherapy

Quinolones are classified in four generations. The first generation quinolones are without fluorine as nalidixic acid, cinoxacin and oxolinic acid; the second generation are norfloxacin, CPFX, OFLX, enoxacin and lomefloxacin; the third generation are LVFX, SPFX and GFLX and the fourth generation are MFLX and trovafloxacin (TVFX) [31]. Most recent FQs are being evaluated as potential anti-TB drugs, also for the shorten TB treatment duration, one of the major strategies for TB control [32]. The use of LVFX or MFLX for the treatment of extensively XDR-TB, defined as resistance to INH, RIF, a FQ and a second-line injectable drug, even when OFLX resistance is present [33]. Fluorine-containing nalidixic acid derivatives, the FQs, were introduced into clinical practice in the 1980s [31]. Norfloxacin, the first of a new generation of FQ are antibacterial activity [34]. Substitutions of the FQ molecule resulted in the development of CPFX, a widely used broad spectrum antimicrobial agent [35]. Several modifications of the FQ structure have been attempted in order to develop new expanded antimicrobial agents with improved pharmacokinetic profiles, decreased resistant mutants, reduced adverse effects, and improved efficacy [36,37]. Last-generation FQs share a broad-spectrum antimicrobial activity covering aerobic and anaerobic Gram-positive and Gram-negative bacteria as well as mycobacteria (M. leprae, M. tuberculosis, M. avium, M. fortuitum, M. intracellulare, M. kansasii, M. marinum, M. smegmatis and M. xenopi) [38,39]. Fluoroquinolones are widely used for the treatment of infections of the respiratory, gastrointestinal and urinary tracts, sexually transmitted diseases, skin and soft tissue infections and chronic osteomyelitis [40,41]. New FQs are in various phases of clinical development like tosufloxacin, fleroxacin, clinafloxacin, gemifloxacin, rufloxacin, enrofloxacin, difloxacin, amifloxacin, iloxacin, temafloxacin, nadifloxacin, grepafloxacin, balofloxacin, pazufloxacin, prulifloxacin, sitafloxacin, garenoxacin, olamufloxacin [42,43]. In particular MFLX and GFLX are undergoing phase III trials [44,45]. Appreciable efficacies of FQs have also been demonstrated against both M. fortuitum infection [46], M. kansasii, and M. xenopi [47]. Many new FQs indicated for the treatment of respiratory tract infections show excellent activity against MAC isolates [48,49]. The effective antimicrobial activity and clinical efficacy of SPFX, LVFX and GFLX are against MAC infection [50,51]. The FQs also exert clinical efficacy against mycobacteria when they are administered in combination with other drugs including RIF, INH, PZA, ethambutol, and some AGs [52-56]. The value of FQs in the treatment of TB infections may be attributed to the good penetration into infected macrophages where they exert antibacterial activity [57]. Selected quinolones, on the intracellular activity against M. tuberculosis as follows: SPFX and sitafloxacin > LVFX and WQ- 3034>olamufloxacin>CPFX and OFLX [58]. Certain drugs, such as rifampin, rifabutin, isiniazid, clofazimine, and some FQs, strongly or moderately reduced the anti-MAC activity [59]. The major problem linked with the use of FQs is the increased incidence of FQ- resistant strains of M. tuberculosis, attitude coupled with the absence of cross-resistance or antagonism with other classes of anti-TB agents. Finally, the emergence of MDR-TB strains is related to previous TB treatment of patients with FQs [3].

Pharmacokinetics

The common adverse effects associated with the use of FQs are gastrointestinal disturbances, nervous system complaints (dizziness, headache), and allergic reactions (skin rashes and pruritus) [60,61]. The use of several FQs have been severely restricted because of advers effects; clinafloxacin causing phototoxicity and hypoglycaemia, SPFX causing phototoxicity [62]. and TVFX causing hepatotoxicity [63]. Grepafloxacin has been withdrawn from the market due to prolongation of the QTc interval. Other FQs such as GFLX, gemifloxacin, LVFX and MFLX have toleraility issues comparable to CPFX. Drug interactions are limited and are infrequent between FQs and other antit-TB drugs [64], however FQ absorption may be reduced when co administered with antacids containing multivalent cations [65,66]. The mechanism by which quinolones enter the bacterial cell is complex [67]. The physicochemical properties of quinolones (hydrophobicity, charge or molecular mass) are important factors for bacterial cell penetration and play a different role in Gram-negative and Gram-positive bacteria. Increasing molecular mass and bulkiness of substituents at C-7 position hinder penetration of quinolones into Gram-negative bacteria through the porin channels, although hydrophobic molecules appear to enter via the lipopolysaccharide or across the lipid bilayer [68]. Gram-positive bacteria do not possess an outer membrane, therefore lacking outer membrane proteins and lipopolysaccharide. Intracellular accumulation observed in Gram-positive bacteria (e.g. S. aureus) is thought to take place by simple diffusion across the cytoplasmic membrane [69]. The unique cell wall structure of mycobacteria is rich in long-chain fatty acids such as C60 to C90 mycolic acids [39]. Mycolic acids are covalently linked to the peptidoglycan-associated polysaccharide arabinogalactan. Moreover, mycobacterial porins, the water-filled channel proteins which form the hydrophilic diffusion pathways, are sparse [70]. A major porin of M. smegmatis, MspA, forms a tetrameric complex with a single central pore, but the density of this protein is 50-fold lower than that of porins of gram- negative bacteria [71]. The mycobacterial cell wall functions as an even more efficient protective barrier than the outer membrane of gram-negative bacteria and limits the access of drug molecules to their cellular targets (Table 2).

Table 2: Classification on the basis of spectrum of activity.

Structure-activity relationship

The minimal quinolone structure consists of a bicyclic system with a substituent at position N-1, a carboxyl group at position 3, a keto group at position 4, a fluorine atom at position 6 (in case of FQs) (Figure 1) and a substituent (often nitrogen heterocycle moiety) at the C-7. Normally in position 2 there are no substituents, various 1-methyl-2-alkenyl-4(1H)quinolones have been investigated as anti-TB agents [72,73]. The DNA gyrase is most likely the only target of quinolone in M. tuberculosis. The DNA supercoiling inhibition assay may be a useful screening test to identify quinolones with promising activity against M.tuberculosis [74]. They measured the inhibition of DNA supercoiling (IC₅₀) and MIC of several quinolones (Table 3).

Table 3: MIC (μg/mL) of Selected quinolones against Mycobacterium Species (Jacobs. 2004).

Figure 1: Minimal quinolone structure.

Some quinolones showed high inhibitory activity against M.tuberculosis DNA gyrase, with IC value below 10 μg/mL. Structure activity relationship (SAR) showed that C-8 with or lacking a substitution, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are advantageous structural features in targeting M. tuberculosis gyrase. The quinolones that showed high potency against M. tuberculosis gyrase are highly active against gram-positive bacteria and definitely were developed for pneumococci (sitafloxacin, SPFX, clinafloxacin, MFLX, and GFLX). Compounds (grepafloxacin, gemifloxacin, TVFX, and the des[6] FQ garenoxacin) with high activity against pneumococci showed only moderate activity against M. tuberculosis gyrase. Most of the FQs developed for their activity against gram negative bacteria (norfloxacin, pefloxacin, enoxacin, fleroxacin, OFLX, temafloxacin, and tosufloxacin) had moderate IC value except for LVFX and CPFX, which had low IC value against M. tuberculosis gyrase. In contrast to its effects against pneumococci, the presence of a group at C-5 [75]. or a substituent in the 7-piperazinyl ring [37]. does not seem to improve gyrase affinity. Moreover, the presence of a naphthyridone core (N-8) in gemifloxacin, which has the lowest MIC against gram-positive bacteria, seems adverse effect for a interaction with M. tuberculosis gyrase. Similarly, the naphthyridones tosufloxacin and enoxacin, were only moderately active [76-84]. In general, β-keto carboxylic acid moiety is required for hydrogen bonding interactions with DNA bases in the single stranded regions of double helix of DNA created by the action of the enzyme, and therefore it is essential for the activity [85]. The substituent at N-1 and C-8 positions should be relatively small and lipophilic to enhance self-association. While at C-6 and C-7 positions at fluorine atom and amino group, respectively, appear to be the best. In particular fluorine atom at C-6 improves cell penetration and gyrase affinity [66,85]. The nature of substituent at C-7 position has a great impact on potency, spectrum, solubility and pharmacokinetics. Almost all quinolones have nitrogen heterocycles linked to this position through the heterocyclic nitrogen, extensively investigated are piperazin-1-yl and its 4-substituted derivatives [86]. e.g. various 7-substituted derivatives of CPFX and GFLX (Figure 2), where derivatives bearing R=H and R₁=NNHCONH₂ were the most active compounds) have been evaluated for anti-TB activity against M. tuberculosis H37Rv, MDR-TB and XDR-TB strains and for inhibition of the supercoiling activity of DNA gyrase from M. tuberculosis and M. smegmatis. The resulst revealed that usually the increase of lipophilic character of the side chain at C-7 improves the anti-TB activity, without inducing cytotoxicity as demonstrate for balofloxacin ethylene isatin derivatives [87]. Anti-TB activity of cephalosporin conjugates with the piperazinyl ring (Figure 3) at C-7 of the CPFX, both able with antibacterial activity and anti-TB activity [88]. Furthermore, with regard to the substituent at N-1 position, studies confirm that the anti-TB activity is higher for the cyclopropyl and tert-butyl goup than for the 2,4-difluorophenyl and others groups [89,90].

Figure 2: Ciprofloxacin and gatifloxacin 7-substituted derivative.

Figure 3: Ciprofloxacin-cephaloosporin conjugates.

Extensive SAR study showed that an increase in the activity of a given quinolone against gram-positive bacteria does not necessarily lead to increased activity against M. tuberculosis [91]. ABT-492 (WQ-3034) is a new FQ that differs from other members of the class by two structural features: a 6-amino-3,5-difluoropyridinyl moiety at position 1 and a 3-hydroxyazetidine-1-yl moiety at position 7 of the 6-FQ core. The antibacterial activity of ABT-492 was significantly greater than that of LVFX. ABT-492 was also more potent than TVFX and CPFX against most quinolone-susceptible pathogens responsible for respiratory tract, urinary tract, bloodstream, and skin infections and against anaerobic pathogens. It was significantly more active than other quinolones against quinolone-resistant gram-positive strains. Furthermore ABT-492 was active against Chlamydia trachomatis, indicating good intracellular penetration. Finally, ABT-492 had improved activity against antibiotic-resistant respiratory tract pathogens, including MDR S. pneumoniae strains and Haemophilus influenzae strains with mutations in DNA gyrase and topoisomerase IV that render them resistant to LVFX [43,92]. However the activity of ABT-492 against M. tuberculosis is comparable to or somewhat weaker than that of LVFX and is significantly lower than that of SPFX. The HSR-903 is a newly synthesized quinolone with superior activity against gram-positive cocci [89]. Finally, complexes of the most potent FQs with Pd(II) and Pt(II) ions have been evaluated. Compounds cis- [MCl₂(L)], where L=ciprofloxacin, LVFX, ofloxacin, SPFX, and GFLX, show good anti-TB activity against M. tuberculosis H37Rv [93].

Conclusion

Quinolines are second-line anti-TB drugs, since their use in TB treatment still remains controversial [94]. On the contrary, they are suggested and recommended in managing MDR-TB, due to the fact that they have a broad and potent spectrum of activity and can also be administered orally, giving a better chance of cure and preventing the development and spread of further resistance [95]. The 4-quinolones-3-carboxylic acid motif, typical of quinolones, have also recently been reported to display “non-classical” biological activities, such as antitumor, anxiolitic, anti-ischemic, anti-HCV-NS3 helicase and NS5B polymerase activities, anti- HSV-1, anti-HIV-1 integrase and CB-2 agonists [96-98]. However, quinolones remain one of the most widely prescribed antibiotics. In conclusion, we can confirm that in general quinolones are particularly adapted to be used as antitubercular agents.

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