in understanding of structure activity relationships with fluoroquinolones has The mechanism of action of quinolones is through theinhibition of bacterial. The anti-TB property mode of action and structure activity relationship studies of the some known quinolone derivatives are studied. Furthermore, the activity of. Abstract. Recently, understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has.
Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action. For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity.
Optimizing overall molecular configuration enhances the number of intracellular targets for antimicrobial action R-8 and impedes the efficiency of efflux proteins R-7 that diminish intracellular penetration. Despite predictions that the incidence of infectious diseases would diminish, the rates of infection with new and reemerging pathogens is increasing, threatening the overall human health [ 1 ].
Approximately half of this increase was due to the HIV epidemic, and the other half was due to infection with emerging and reemerging pathogens [ 2 ]. Ongoing discoveries of new infectious diseases and an explosion of drug resistance in organisms for which the associated illness was once thought to be cured have dramatically altered the practice of medicine within the hospital, and is beginning to effect the management of infections in the ambulatory care setting.
The quinolone class of antimicrobial agents has been developed, and grown, within this time frame [ 3 ]. Despite ongoing development of new agents in this important class, resistance to newly released agents continues to be observed [ 4 ]. Recent data suggests emerging resistance is specifically linked to use of some of the older compounds [ 55a ].
We have learned much about how structural modifications affect both activity and toxicity. A recent report assessed the toxicity profiles of newer fluoroquinolone agents [ 6 ], and this topic will not be addressed here. An excellent summary of structure-activity relationships by Tillotson [ 7 ] was published inbut considerable new information has been learned since that time. Much can be inferred about the overall effect s of various chemical modifications by better understanding how microbes become resistant to the action of fluoroquinolones.
A comprehensive discussion of this topic was recently published [ 8 ]. The focus of my current review is the most recent data on how various structural modifications affect the activity of quinolones, interpreting structural effects in the light of work on emerging microbial resistance, and highlighting ongoing drug development that points to a continued useful future for this important class of antimicrobial agents.
Our understanding of cellular function at the molecular level progressed impressively as we ended the 20th century. One interesting observation has been that bacteria appear uniquely fitted for survival in that they seem designed to multiply ceaselessly as long as required nutritional support is available [ 9 ].
Thus, design and synthesis of agents that rapidly exert their antimicrobial effect, and have a low propensity for permitting resistant strains to emerge, appear intuitively necessary directions. The gyrase is a tetramer composed of 2 subunits, one encoded by the gyrA gene and one encoded by the gyrB gene.
Topoisomerase IV is believed to partition intertwined, replicated chromosomes before cell separation division can take place. The 2 subunits of this tetrameric enzyme are encoded by the parC and parE genes referred to as grlA and grlB in Staphylococcus aureus. These functional enzymes cleave double-stranded DNA the G or gate-segmentpass another strand of duplex DNA through the break the T or transported-segmentand then anneal the broken G strand, using ATP as an energy source [ 810 ].
Both the G segment and the T segment are then released from the enzyme. Fluoroquinolones are thought to stabilize i. The elegant crystal structure of the partial DNA gyrase protein has been published [ 11 ], and one can see from this representation the close association between various DNA mutations associated with resistance to drug action and the active tyrosine sites of the enzyme.
Presumably, topoisomerase IV functions similarly. Because the DNA gyrase and topoisomerase IV enzymes interact with DNA in a similar manner, quinolone action on either of them can be lethal to the bacterial cell. Further evidence for this concept was recently reported by Fournier and colleagues [ 11a ]. Early findings of clinically significant bacterial resistance to the quinolones typically implicated mutations in highly conserved amino acid residues of the so-called quinolone resistance determining region QRDReither in the GyrA subunit of DNA gyrase or the ParC subunit of topoisomerase IV.
It is of interest that the initial targets of fluoroquinolone action seem reversed in gram-negative and gram-positive species. For example, in gram-positive organisms like S.
Mutations at the equivalent positions of the GyrA subunit of DNA gyrase are secondary events and lead to very high levels of resistance, presumably by making both topoisomerase IV and gyrase highly resistant to fluoroquinolone binding. Whereas most quinolone antimicrobials appear to have a preferential affinity for topoisomerase IV in gram-positive bacteria, sparfloxacin is reported to first interact with target GyrA, because mutations in strains selected on exposure to this fluoroquinolone accumulate primarily in gyrA [ 18 ], suggesting specific structural modification has a profound impact on drug-target interaction.
Other pathways for development of resistance to quinolone antimicrobial agents also exist. Notably, there are no known enzymes that degrade the fluoroquinolone antimicrobial agents. Thus, the routes microbes have toward developing a resistance phenotype involve target alteration e. Interestingly, they appear particularly active against compounds that cannot be inactivated or degraded, as is the case for the fluoroquinolones.
In addition, commonly used compounds such as salicylates are able to increase resistance to fluoroquinolones [ 23 ], likely through activation of an efflux system s. All this evidence suggests the importance of active efflux as mechanism that initially allows bacteria to survive [ 2425 ] and subsequently permits the development of adaptive QRDR mutations at key drug target sites.
Energy-dependent efflux has been reported in both S. Structural differences among fluoroquinolones, notably overall molecular hydrophobicity and bulkiness of the C-7 substituent, are now thought to influence the efficiency of efflux [ 333536 ]. Similar efflux systems are also known to be important for expression of resistance in gram-negative bacteria [ 37 ].
Thus, Nikkado has recently hypothesized that design of agents less susceptible to efflux may be a good strategy for combating microbial resistance [ 36 ]. Modifications at Specific Positions on the Quinolone Molecule Figure 1 shows the general structure for the quinolone molecule and uses the accepted numbering scheme. Figure 1 View large Download slide Structure of the quinolone molecule, using the accepted numbering scheme for positions on the molecule.
An R indicates possible sites for structural modification.
Molecules at positions marked by a dashed box can also be changed; however, the most commonly used structure is shown here. This position is part of the enzyme-DNA binding complex, and has a hydrophobic interaction with the major grove of DNA [ 38 ].
A cyclopropyl substituent is now considered the most potent modification here, followed by addition of a 2,4-difluorophenyl [ 39 ]. Most other substituents, including one with only the wrong stearic position R -ofloxacin can presumably lower the number of molecules capable of binding to the enzyme-DNA pocket, and therefore reduce potency [ 40 ].
Interestingly, ofloxacin has a tricyclic ring structure with a CH3 attached to the asymmetric C-3 position on the oxazine ring, thus connecting positions 1 and 8 with a fused ring. Although this has been a useful alternative to the cyclopropyl substituent, the S- isomer exhibits twice the order of magnitude of activity as the R- isomer, which seems to determined by the number of molecules that can be assembled, or stacked, in the enzyme-DNA complex binding pocket [ 40 ].
Even the potency of the purified S- isomer fused ring is less than that of the cyclopropyl substituent, suggesting the difficulty of improving upon this latter modification. This location is very close to the site for DNA gyrase or topoisomerase IV binding so it is believed that any added bulk inhibits access and results in a lower level of microbiological activity [ 739 ].
Norfloxacin is superior to tetracyclines in decreasing the duration of diarrhea in cholera. Shigellosis is treated effectively with either CPFX or azithromycin [ 22 ]. The FQs have activity against the respiratory pathogens, like H. The FQs have been very effective against both H. Mild to moderate activity exhibited against P. The newer FQs are used as single agents for treatment of community-acquired pneumonia [ 11 ]. However, have decreasing susceptibility of S.
Bone, Joint, and Soft Tissue Infections The treatment of chronic osteomyelitis requires prolonged antimicrobial therapy with agents active against S. 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. Failures have been associated with the development of resistance in S.
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. Other Infections Ciprofloxacin CPFX wide usage for the prophylaxis of anthrax and also effective for the treatment of tularemia [ 2627 ]. 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.
Quinolones, when used as prophylaxis in neutropenic patients, have decreased the incidence of gram-negative rod bacteremias. Diarrhea and antibiotic-associated colitis have been unusual. CNS side effects like mild headache and dizziness, in 0.
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. 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.
Approved clinical uses for selected fluoroquinolones. Quinolones and Chemotherapy Quinolones are classified in four generations.
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 ]. Fluorine-containing nalidixic acid derivatives, the FQs, were introduced into clinical practice in the s [ 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 [ 3637 ]. Last-generation FQs share a broad-spectrum antimicrobial activity covering aerobic and anaerobic Gram-positive and Gram-negative bacteria as well as mycobacteria M.
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 [ 4041 ]. 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 [ 4243 ].
Appreciable efficacies of FQs have also been demonstrated against both M. Many new FQs indicated for the treatment of respiratory tract infections show excellent activity against MAC isolates [ 4849 ]. 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. 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.
Study of Antimicrobial Quinolones and Structure Activity Relationship of Anti-Tubercular Compounds
Pharmacokinetics The common adverse effects associated with the use of FQs are gastrointestinal disturbances, nervous system complaints dizziness, headacheand allergic reactions skin rashes and pruritus [ 6061 ]. The use of several FQs have been severely restricted because of advers effects; clinafloxacin causing phototoxicity and hypoglycaemia, SPFX causing phototoxicity [ 62 ].
Grepafloxacin has been withdrawn from the market due to prolongation of the QTc interval. 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 [ 6566 ].
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. 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. 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. 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 Normally in position 2 there are no substituents, various 1-methylalkenyl-4 1H quinolones have been investigated as anti-TB agents [ 7273 ].
The DNA gyrase is most likely the only target of quinolone in M. The DNA supercoiling inhibition assay may be a useful screening test to identify quinolones with promising activity against M. Some quinolones showed high inhibitory activity against M. 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.
The quinolones that showed high potency against M. Compounds grepafloxacin, gemifloxacin, TVFX, and the des[ 6 ] FQ garenoxacin with high activity against pneumococci showed only moderate activity against M.
In contrast to its effects against pneumococci, the presence of a group at C-5 [ 75 ]. 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. Similarly, the naphthyridones tosufloxacin and enoxacin, were only moderately active [ 76 - 84 ]. 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 [ 6685 ].
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 piperazinyl and its 4-substituted derivatives [ 86 ].
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 ].
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 [ 8990 ]. Ciprofloxacin and gatifloxacin 7-substituted derivative.
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. ABT 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 was active against Chlamydia trachomatis, indicating good intracellular penetration.
However the activity of ABT against M. The HSR is a newly synthesized quinolone with superior activity against gram-positive cocci [ 89 ]. 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 ].
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. The history of quinolones In Fluoroquinolone Antibiotics. Fluoroquinolones tuberculosis and resistance. Fluoroquinolone resistance in patients with newly diagnosed tuberculosis.
N Engl J Med. World Health Organization HIV infection associated tuberculosis: Clin Infect Dis, ; Accelerated course of human immunodeficiency virus infection after tuberculosis.