Discovery of novel halogenated 8-hydroxyquinoline-based anti-MRSA agents: In vitro and QSAR studies.

Methicillin-resistant Staphylococcus aureus (MRSA) infection has been considered to be one of global health problems due to limited classes of effective antimicrobial drugs. Herein, 8-hydroxyquinoline (8HQ) and its derivatives (1-7) were investigated for their anti-MRSA and antioxidant activities. Cloxyquin (2), a halogenated 8HQ, exerted the highest antimicrobial activity (MIC50 ≤ 5.57 µM) with high safety index, whereas an amino-derivative 7 showed the strongest antioxidant activity. Additionally, quantitative structure-activity relationship (QSAR) study demonstrated that mass, polarizability, topological charge, and van der Waals volume are essential properties governing the anti-MRSA activity. Taken together, cloxyquin was highlighted as a promising compound for further development as a novel anti-MRSA agent. QSAR findings would also benefit for further rational design of novel 8HQ-based compounds to combat the MRSA resistance.

Nitroxoline: a potent antimicrobial agent against multidrug resistant Enterobacteriaceae.

Antimicrobial resistance has become a prime global concern. An ability of the microbes to produce enzymes to destroy antimicrobial drugs is one of the well-known mechanisms underlying the resistance. 8-Hydroxyquinoline (8HQ) and derivatives were reported to exert diverse biological effects such as antimicrobial, antioxidant and antineurodegenerative activities. Herein, 8HQ (1), nitroxoline (NQ, 2) and 7-Br-8HQ (3) were investigated for antimicrobial activity against Enterobacteriaceae including extended spectrum ß-lactamase (ESBL)-producing and carbapenemase-producing strains as well as the effect of metal ions. These compounds (1-3) displayed the great antimicrobial activity against fifty-eight bacterial isolates of Escherichia coli, Providencia rettgeri and Klebsiella pneumoniae, in which NQ (2) exerted the highest antimicrobial activity with a MIC50 of 42.04 µM (8 µg/mL) and MBC50 of 168.28 µM (32 µg/mL). The MIC values of NQ (2) and 7-Br-8HQ (3) were significantly increased in the presence of Cu2 + and Fe3+. This finding reveals that NQ could be an effective compound to be further developed as an antimicrobial agent for combating Enterobacteriaceae infections.

Repositioning of 8-hydroxyquinoline derivatives as a new promising candidate for combating multidrug resistant Neisseria gonorrhoeae.

The multidrug resistance of Neisseria gonorrhoeae becomes a public health problem worldwide, especially the strain H041 that showed the decrease susceptibility to ceftriaxone which is the last resort for gonorrhea treatment. Therefore, the simultaneous discovery and development of a new compound to fight this pathogen is urgently required. In this study, 8-hydroxyquinoline (8HQ) and derivatives were evaluated for their antimicrobial activities against the gonococcal pathogen using spectinomycin as the reference drug. The results showed that 8HQ derivatives gave an excellent antimicrobial potency. Particularly, the dihalogenated 8HQ (iodoquinol, clioquinol and 5,7-diCl-8HQ) exerted the high activity with MIC range of 0.08-0.15 µM, 0.10-0.20 µM and 0.28-0.56 µM, respectively, compared with the reference drug (MIC = 16 µg/mL or 48.14 µM). Moreover, these compounds were also shown to be non-cytotoxic/very high safety index. The findings reveal that these three compounds could be further developed as a new antimicrobial agent for fighting the gonorrheal disease.

Derivatives (halogen, nitro and amino) of 8-hydroxyquinoline with highly potent antimicrobial and antioxidant activities.

8-Hydroxyquinoline (8HQ) compounds have been reported to possess diverse bioactivities. In recent years, drug repositioning has gained considerable attention in drug discovery and development. Herein, 8HQ (1) and its derivatives (2-9) bearing various substituents (amino, nitro, cyano and halogen) were investigated for their antimicrobial against 27 microorganisms (agar dilution method) and antioxidant (DPPH method) activities. The parent 8HQ (1) exerted a highly potent antimicrobial activity against Gram-positive bacteria including diploid fungi and yeast with MIC values in the range of 3.44-13.78 µM. Moreover, the halogenated 8HQ, especially 7-bromo-8HQ (4) and clioquinol (6), displayed a high antigrowth activity against Gram-negative bacteria compared with the parent compound (1). Apparently, the derivatives with a relatively high safely index, e.g., nitroxoline (2), exhibited strong antibacterial activity against Aeromonas hydrophila (MIC=5.26 µM) and selectively inhibited the growth of P. aeruginosa with the MIC value of 84.14 µM; cloxyquin (3) showed a strong activity against Listseria monocytogenes and Plesiomonas shigelloides with MIC values of 5.57 and 11.14 µM, respectively. Most compounds displayed an antioxidant activity. Specifically, 5-amino-8HQ (8) was shown to be the most potent antioxidant (IC50=8.70 µM) compared with the positive control (α-tocopherol) with IC50 of 13.47 µM. The findings reveal that 8HQ derivatives are potential candidates to be further developed as antimicrobial and antioxidant agents.

Antimicrobial resistance markers as a monitoring index of gonorrhoea in Thailand.

Multiplex PCR was applied to explore the antimicrobial-resistance profiles of 145 gonococci isolated from Bangrak Hospital, Thailand in 2007. All isolates were clearly identified for the plasmid-mediated resistant types of penicillin (Asia, Africa and Toronto) and tetracycline (American and Dutch). This method can also predict the decreased susceptibility to ciprofloxacin by detection of Ser-91 mutation. Prevalence rates of penicillinase-producing Neisseria gonorrhoeae (PPNG) and high-level tetracycline-resistance N. gonorrhoeae (TRNG) were shown to be high as 82.1% and 84.1%, respectively. Most PPNG carried the Africa-type (78.2%) while the American-type (61.8%) was harboured in most TRNG. Mono- and triple-resistance patterns were presented in 2.6% and 79.5% of male, 20.7% and 62.1% of men who have sex with men (MSM), 0% and 75.0% of female, and 10% and 70% of female sex workers (FSW). Additionally, the rate of the Dutch type was high in patients among the age of 35-44 years (57.1%) and female patients (43.8%). The changing types of plasmids have been noticed during the time period of study. The multi-resistance patterns of the gonococcal isolates can be used as an epidemiological index of gonorrhoea and human sexual behaviours. This information will support the management of individual patients as well as the public health surveillance.

Protocol for a facile multiplex PCR for multi-antimicrobial resistance and Gonococcus detection.

Gonorrhea is a continuing problem worldwide particularly in terms of the spread of multiple drug resistance. We have successfully developed an efficient PCR method for the simultaneous identification of gonococci and detection of the antimicrobial-resistant profile. By this method, penicillinase-producing Neisseria gonorrhoeae (PPNG), high-level tetracycline-resistant N. gonorrhoeae (TRNG), and ciprofloxacin-resistant N. gonorrhoeae (CRNG) can be clearly identified. Moreover, the plasmid-types of penicillin and tetracycline resistance are also characterized. The method has 100 % sensitivity and specificity. It is also time- and labor-saving compared to the conventional method. Thus, the procedure is suitable for epidemiological surveillance.

Antibiograms and randomly amplified polymorphic DNA-polymerase chain reactions (RAPD-PCR) as epidemiological markers of gonorrhea.

The development of antimicrobial resistance of Neisseria gonorrhoeae arising from wide dissemination of resistant clones is a major global health problem. In this study, a total of 235 isolates of N. gonorrhoeae isolated from patients of Bangrak Hospital were tested for their antibiotic susceptibilities to penicillin, norfloxacin, ofloxacin, ciprofloxacin, spectinomycin, and ceftriaxone. Mutation (Ser-91) in the quinolone resistance determining regions of gyrA and random amplification of the polymorphic DNA polymerase chain reaction (RAPD-PCR) were examined from 145 isolates. Among these, 55 isolates were obtained during January-March 2000, 46 isolates during January-March 2002, and 44 isolates during October-December 2002. The occurrence of combination resistance between penicillin and quinolone was 20% in January-March 2000, which was increased to 57.8% during the period of October-December 2002 (P<0.0001). Mutation of Ser-91 in gyrA could be directly linked with the resistance or declining of susceptibility to ciprofloxacin. Using RAPD-PCR, we could classify the 145 isolates into 4 and 5 groups by primers D11344 (5'-AGTGAATTCGCGGTGAGATGCCA-3') and D8635 (5'-GAGCGGCCAAAGGGAGCA GAC-3'), respectively. Combination of the data obtained from these two primers produced 11 fingerprint groups. Our findings conclude that monitoring of the Ser-91 mutation of gyrA and RAPD-PCR methods are most useful for epidemiological screening.

New bioactive triterpenoids and antimalarial activity of Diospyros rubra Lec.

The first investigation of the chemical constituents and bioactivities of Diospyros rubra Lec. is reported. D. rubra extracts were screened for antimicrobial, antimalarial and cytotoxic activities. They were only shown to be active antimalarials. The extracts with good antimalarial activity were isolated and extensively purified to give lupeol (1), lupenone (2), betulin (3), lupeol acetate (4), 28-O-acetylbetulin (5), ß-sitosteryl-3-O-ß-D-glucopyranoside (6) and a mixture of ß-sitosterol and stigmasterol. Some of the isolates were tested for antimicrobial and cytotoxic actions. Betulin (3) displayed antimicrobial activity against Streptococcus pyogenes with a minimum inhibitory concentration (MIC) of 85 µg/mL. Interestingly, bioactive fractions all selectively exerted some antimicrobial activity against Corynebacterium diphtheriae NCTC 10356 with the MIC range of 64-256 µg/mL. The study provides data to support the medicinal importance of the D. rubra.

One-step PCR for the identification of multiple antimicrobial resistance in Neisseria gonorrhoeae.

One-step multiplex PCR was developed for the identification of gonococci and antimicrobial-resistant profiles. From forty Neisseria gonorrhoeae isolates, the penicillinase-producing N. gonorrhoeae (PPNG), the high-level tetracycline-resistant N. gonorrhoeae (TRNG), and the ciprofloxacin-resistant N. gonorrhoeae (CRNG) were successfully classified. Our method provides expediency and benefit to epidemiology and antimicrobial-resistance mobility with 100% sensitivity and specificity for gonococcal-detection. The detection limit was 500 CFU/reaction.