A review on quinoline derivatives as anti-methicillin resistant Staphylococcus aureus (MRSA) agents

Methicillin Resistant Staphylococcus aureus (MRSA) consists of strains of S. aureus which are resistant to methicillin. The resistance is due to the acquisition of mecA gene which encodes PBP2a unlike of any PBPs normally produced by S. aureus. PBP2a shows unusually low β-Lactam affinity and remains active to allow cell wall synthesis at normally lethal β-Lactam concentrations. MRSA can cause different types of infections like Healthcare associated MRSA, Community associated MRSA and Livestock associated MRSA infections. It causes skin lesions, osteomyelitis, endocarditis and furunculosis. To treat MRSA infections, only a few options are available like vancomycin, clindamycin, co-trimoxazole, fluoroquinolones or minocycline and there is a dire need of discovering new antibacterial agents that can effectively treat MRSA infections. In the current review, an attempt has been made to compile the data of quinoline derivatives possessing anti-MRSA potential reported to date.


Introduction
Staphylococcus aureus, a Gram-positive bacterium, is a member of the family Micrococcaceae, whose cells tend to occur either singly or if dividing cells do not separate, form pairs, tetrads and distinctive irregular "grape-like" structures [1]. Staphylococcus aureus is a very important bacterium because it can cause a wide range of diseases such as rashes, inflammations of bones and the meninges as well as septicemia and has a capacity to adapt to different environments [2].

Prevalence of methicillin resistant Staphylococcus aureus (MRSA)
In 1965, MRSA infection in Australia was first recorded in Sydney. First case of hospital MRSA in the United States was reported in Boston in 1968. The first methicillin strain of S. aureus was identified in Europe in the United Kingdom. Till 1970s, MRSA infections in Europe were limited to hospital outbreaks. In Japan, MRSA was detected for first time in 2003. In 2011, China showed a mean MRSA rate of 45.8% among all clinical S. aureus isolates [3].
India is also not an exception in this aspect and high prevalence of MRSA is an emerging health problem. MRSA prevalence in India has significantly increased from 12% in 1992 to 40% in 2009 [4] with minimum incidence of 25% in western India and maximum of 50% in South India [5]. Bouchiat et al. Found that 54.8% of the total S. aureus isolates among samples from a hospital in eastern Uttar Pradesh were methicillin resistant. Further, 57.3% of the blood cultures from a Neonatal Intensive Care Unit in Amritsar were methicillin resistant [6].
Kali et al. studied resistance pattern of methicillin resistant Staphylococcus aureus on one hundred two clinical isolates of MRSA and found that MRSA isolates showed high resistance to co-trimoxazole (82.3%), ciprofloxacin (76.4%), gentamicin (64.7%) and tetracycline (49%) as compared to other drugs [4].

Healthcare associated MRSA (HA-MRSA)
HA-MRSA means MRSA isolates from hospitals and are gradually increasing round the globe. The rate of HA-MRSA infections is high (> 50%) in USA, Asia and Malta. Asian countries like South Korea (77.6%), Vietnam (74.1%), Taiwan (65%) and Hong Kong (56.8%) have higher incidence of HA-MRSA infections. Intermediate rate (25-50%) is reported in Africa, China and Europe. In HA-MRSA, anterior nare is the usual site for MRSA colonization. Hands, perineal region, skin wounds, throat, genitourinary tract and the digestive tract may also colonize MRSA. Generally, HA-MRSA results in dermatitis, septicemias, heart and lung diseases. Risk factors for HA-MRSA include hospitalization, surgery, dialysis and previous history of MRSA infection [2].

Community associated MRSA (CA-MRSA)
Community associated means MRSA isolates from community living away from hospital settings. In 1993, first case of CA-MRSA was reported in Western Australia. Military personnel, prison inmates, athletes, intravenous drug users are at high risk for CA-MRSA. Elderly, children, patients having implanted medical devices, people suffering from diseases like diabetes or neutrophil dysfunction, HIV/AIDS and influenza are also at high risk for CA-MRSA infection [8].

Livestock associated MRSA (LA-MRSA)
MRSA was considered as a human infection until when it was isolated in a dairy cow with mastitis and in pigs [2]. MRSA can transfer from humen to animals and vice versa. Voss et al. reported 23% of pig farmers infected with MRSA from a pig farm in the Netherlands [9] and VanRijen et al. found 32% of farm workers colonized with MRSA [10]. This overcoming of the genus barrier by LA-MRSA strains indicates its host adaptability and shows that livestock animals can serve as a reservoir for infections in humen [8].

Main text
Mechanism of resistance β-Lactam antibiotics inhibit penicillin binding proteins which lead to weakened cell wall and ultimately the cell death. Methicillin resistance in the MRSA strain is due to the acquisition of mec element and mecA gene which encodes PBP2a unlike of any PBPs normally produced by S. aureus; mec element codes for recombinase proteins causing excision and integration of mec element in bacterial chromosome. MecI and MecR1 proteins regulate the synthesis of PBP2a, former being a signal transduction protein and later is a transcription regulator [1]. PBP2a shows unusually low β-Lactam affinity and remains active to allow cell wall synthesis at normally lethal β-Lactam concentrations [11].
Dolan et al. reported the synthesis and antibacterial evaluation of a series of thiourea-containing compounds. All the synthesized compounds were evaluated for their bacteriostatic activity against E. coli, P. aeruginosa and S. aureus. Antibacterial activity results indicated that     (Table 7). Compound 10 was also evaluated for its in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella and was found to be non-toxic to the larvae of Galleria mellonella up to 1000 µg/mL [26]. Perkovic et al. designed and synthesized a series of novel compounds with primaquine and hydroxyl or halogen substituted benzene moieties bridged by urea or bis-urea moiety using benzotriazole as the synthon. The synthesized compounds were tested in vitro for their antimicrobial activity against a panel of 15 bacterial strains and a fungal strain, C. albicans using primaquine and tetracycline hydrochloride (TC) or voriconazole (VOR) as standard drugs. Antimicrobial activity results showed that only four compounds (11)(12)(13)(14) were having good antibacterial/antifungal effect. The most potent compound, 14 was having MIC value ranged from 1.6 to 12.5 µg/mL against the selected bacterial strains including MSSA [27].
Takahashi et al. examined effect of indolo[3,2-b]quinoline derivatives on hemolysis induced by the aerolysin-like hemolysin (ALH) of Aeromonas sobria and also by the alpha hemolysin of Staphylococcus aureus. They observed that hemolysis induced by ALH was significantly reduced by all four derivatives while alpha mediated hemolysis was significantly reduced by three of them. Compounds 15 and 16 having amino group at the C-11 position of indolo [3,2-b]quinoline, showed strong ALH inhibitory activity and compound 17 consisting benzofuran and quinoline displayed strong alpha-hemolysin inhibitory effects [28].    Wang et al. synthesized a series of 2-phenyl-quinoline-4-carboxylic acid derivatives and evaluated their antibacterial activities against Escherichia coli, Pseudomonas method, which indicated that compound 18 was most potent compound against MRSA having zone of inhibition 5 ± 0.5 and 6 ± 0.2 mm at 50 and 100 µg/mL respectively. Further, MTT assay displayed the low cytotoxicity of compound 18 [29].

18
Zhang et al. synthesized a series of benzimidazole quinolones as potential antimicrobial agents. The synthesized compounds were screened for their antimicrobial activity against a group of Gram positive and Gram negative bacterial strains. The compounds were designed with an aim to overcome the resistance against quinolones. Literature studies reveal that C-7 position of quinolones is in closed proximity to the Arg456 in the topoIV-DNA complex, mutation in which leads to resistance making the quinolone C-7 position a site of strategic importance in overcoming the resistance. Moreover substituents at C-7 influence the cell permeability and effect the bacterial resistance. In order to modify quinolone C-7 position, benzimidazole moiety was introduced. Antibacterial activity results showed that compounds 19-22 were found to be the most potent antibacterial agents against MRSA, each having MIC value 0.125 µg/mL (    Huang et al. synthesized a series of levofloxacin corebased derivatives and were screened them for their antimicrobial activity against selected bacterial strains. Antibacterial screening results indicated that compounds 25-28 were most potent anti-MRSA agents each having MIC value 1 µg/mL (Table 10) [32].
Zhang et al. designed and synthesized a series of fluoroquinolone derivatives containing 3-alkoxyimino-4-(cyclopropylanimo)methylpyrrolidine moiety and evaluated their antibacterial activity against a panel of Gram-negative and Gram-positive strains. The antibacterial activity results indicated that compound 29 was found to be most potent MRSA inhibitor having MIC values of 2 µg/mL against both MRSA 14-4 and 14-5 strains (Table 11) [33].   . The compounds were designed with an aim to overcome the resistance against quinolones. Literature studies reveal that N-1 position of quinolones is in closed proximity to the residues Ser79 and Asp83 in the topoIV-DNA complex, mutation in which leads to resistance making the quinolone N-1 position a site of strategic importance in overcoming the resistance. In order to modify quinolone N-1 position, nitroimidazole moiety was introduced based on their previous studies with a possibility of its non-covalent interactions with DNA base and thus overcoming the resistance. The antibacterial activity results indicated that compound 30 was most potent anti-MRSA agent with MIC value 1 µg/mL and was more potent than standard drugs chloromycin and norfloxacin (MIC values 8 and 2 µg/mL respectively, Table 12). Mechanism of action of compound 30 was investigated by studying its interactions with calf thymus DNA which showed non-covalent interaction between compound 30 and topo IV DNA complex, especially hydrogen bonds between compound 30 and Ser79 [34].
Abouelhassan et al. synthesized a series of quinoline derivatives having potent biofilm dispersal activity against methicillin-resistant S. aureus. They found that 9 out of 11 synthesized compounds were having better biofilm clearing activity than standard drug nitroxoline (Ec 50 value 10.5 µM) and compound 31 was most potent and effective in clearing the biofilm established by MRSA-2 strain with an EC 50 value 2.06 µM (Table 13) [35].
Cui et al. synthesized a novel series of quinolone triazoles and characterized it by using spectral techniques. The compounds were designed based on the results of their previous study indicating the importance of triazolyl ethanol moiety in the C-7 side chain of ciprofloxacin. Introduction of triazole ring at N-1 position of quinolones also improved their antimicrobial activity. Based on the improved antimicrobial activity of hybrid compounds containing quinolone and triazole moiety, triazolyl ethanol fragment into the N-1 position was incorporated. The synthesized compounds were screened for their antimicrobial activities against seven bacterial and four fungal strains including MRSA. The antibacterial activity results indicated that compound 32 was found to be most potent antibacterial agent against MRSA with an MIC value of 0.5 µg/mL (Table 14). Mechanism of action of compound 32 was investigated by studying its interactions with calf thymus DNA by fluorescence and UV-vis absorption spectroscopy results of which indicated that compound    (Table 16) [38].
Cieslik et al. synthesized a series of new ring-substituted styrylquinolines and two oxorhenium complexes. The synthesized compounds were screened for their antimicrobial potential against a panel of bacterial and fungal strains which indicated that compound 38 was the most potent anti-MRSA agent having MIC/IC 90 value of 3.9 and 7.81 µmol/mL at 24 and 48 h respectively and was more potent to all standard drugs bacitracin, penicillin V and ciprofloxacin (Table 17) [39].
Sevgi et al. synthesized novel glyoximes containing quinoline moiety. The antibacterial activity of synthesized compounds was tested against selected bacterial strains. The antibacterial activity results indicated that only compound 39 showed good anti-MRSA activity (zone of inhibition = 12 mm) and was equipotent with standard drugs Amoxicillin/Clavulanic acid and Gentamicin (Table 18) [40].
Wu et al. synthesized a series of 9-bromo-substituted indolizinoquinoline-5,12-dione derivatives. The synthesized compounds were evaluated for their antimicrobial activity against representative bacterial and fungal strains. The antimicrobial activity results indicated that          (Table 25) [47].
Hoemann et al. discovered a novel series 2-(1H-indol-3-yl)quinolones as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents from a combinatorial library. The synthesized compounds were having minimum inhibitory concentrations (MICs) < 1.0 mg/mL against MRSA. A structure activity relationship (SAR) study was conducted for the anti-MRSA activity of synthesized quinolones which indicated that compounds having chloro or methyl alcohol group at 4th position of quinoline ring were having best anti-MRSA activity. Presence of chloro group at 5th, 6th, 7th and 8th position of quinoline ring also improved anti-MRSA activity of synthesized compounds. Presence of halo groups (Cl, Br or F) at 5th or 6th positions of indole nucleus also improved the anti-MRSA activity of the synthesized compounds. Compound 51 ((2-(5-bromo-1H-indol-3-yl)-7-chloroquinolin-4-yl) methanol) was found to be the most potent compound of the series (Table 27) [49].

Conclusion
The literature reports reveal that quinoline derivatives have immense potential to control MRSA infection. Many compounds have shown anti-MRSA activity better than standard drugs that too with low toxicity but microbes are also having an evolutionary feature of resistance. We have very limited options to deal with these emerging resistant microbes. So, we have to keep our war against emerging resistant microbes on and also we have to check the abuse of available antibiotics. This review will definitely help the researchers working on development of novel anti-MRSA agents.