In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis

Rodrı́guez, Juan Carlos; Ruiz, Montserrat; Climent, A.; Royo, Gloria

doi:10.1016/s0924-8579(00)00337-x

Cited by 82 publications

(61 citation statements)

References 20 publications

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“…d In addition, because of the high oral bioavailability, generally good tolerability, and low-to-moderate cost, they are currently in phase III of clinical trials for an evaluation of their potential to shorten TB treatment when in combination with other anti-TB agents (7). If successful, these drugs could shift from second-line antituberculars to first-line (8)(9)(10). However, mainly because of the recurrent use of quinolones for infections in patients where TB initially was not suspected, resistance to these two agents is a matter of concern (11,12).…”

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confidence: 99%

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

et al. 2012

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The screening of an in-house quinolones library against Mycobacterium tuberculosis (Mtb) H 37 Rv, followed by a first cycle of optimization, yielded 6-hydrogen-8-methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non-replicating state (NRP-TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai, characterized by a properly substituted piperidine at the C-7 position, were active against single-drug-resistant (SDR-TB) Mtb strains, maintaining overall good potency also against ciprofloxacin-resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C-6 position. Further elaboration of the 6-hydrogen-8-methylquinolone scaffold, with a particular focus on the C-7 position, is expected to give even more potent congeners holding promise for shortening the current anti-TB regimen.Key words: 6-desfluoroquinolones, antitubercular agents, multidrug resistance, non-replicating bacteria, quinolone SAR Abbreviations: 6-DFQs, 6-desfluoroquinolones; CipR, ciprofloxacinresistant; DOTS, Directly Observed Therapy Short-course; EMB, ethambutol; FQs, fluoroquinolones; INH, isoniazid; LORA, low oxygen recovery assay; MABA, microplate Alamar Blue assay; MBC, minimum bactericidal concentration; MDR-TB, multidrug-resistant Mtb; MIC, minimum inhibitory concentration; Mtb, Mycobacterium tuberculosis; NCEs, new chemical entities; NRP-TB, non-replicating persistent Mtb; PZA, pyrazinamide; RMP, rifampin; SAR, structure-activity relationships; SDR-TB, single-drugresistant Mtb; TB, tuberculosis; XDR-TB, extensively drug-resistant Mtb.Received 3 May 2012, revised 31 July 2012 and accepted for publication 2 August 2012 Tuberculosis (TB) is an old and re-emerging disease that spreads at alarming rate. Mycobacterium tuberculosis (Mtb) is responsible for 8.8 million new active cases and 1.5 million deaths in 2010, and one-third of the world's population is estimated to be latently infected with TB. About 95% of the tuberculosis cases and deaths occur in the developing countries, but there has also been a recent, highly publicized, resurgence of TB also in developed ones.a This pandemic is complicated by the co-infection with HIV (15% of new cases worldwide are HIV positive) and the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) Mtb strains.b The current recommended therapeutic strategy, namely Directly Observed Therapy, Short-course (DOTS) is based on the co-administration of four drugs, namely rifampin (RMP), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by a prolonged treatment with INH and RMP for an additional 4-7 months.c The cause of the long-period treatment is the peculiar ability of Mtb to survive in a non-replicating persistent (NRP-TB) state while withstanding chemotherapy. These features highlight the need to develop well-tolerated...

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6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

et al. 2012

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“…Higher daily oral doses of CFX (1500 mg), OFX (800 mg) and LFX (1000 mg) have also been used safely in TB patients with normal renal functions [28,30] • SM = 0.5-2.0 mg/l. The EBA (0-2 days) of MFX and GFX and high dose LFX (and to a lesser extent high dose OFX) is close to or equal to that of INH (recorded as 0.5-0.6 at oral dose of 300 mg), which is regarded as the most effective anti-TB drug in the intensive phase of chemotherapy [32][33][34][35][36]. The CFX is the least effective FQ against M. tuberculosis as the EBA of even high dose CFX is quite low (Table I).…”

Section: Fluoroquinolones As Anti-tb Drugsmentioning

confidence: 93%

Role of fluoroquinolones in the treatment of tuberculosis

Ahmad

Mokaddas

2011

RHC

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“…One possibility is that moxifloxacin interferes with protein synthesis in slowly metabolising bacteria through a mechanism that differs from that used by RIF. In mouse models the activity of moxifloxacin against tubercle bacilli was comparable to that of INH [79]. Moreover, when used in combination with moxifloxacin and PZA, moxifloxacin has been reported to kill the bacilli more effectively than the INH+RIF+PZA combination [85], [87].…”

Section: Moxifloxacinmentioning

confidence: 96%

“…Lately, the interest on FQs as anti-TB agent has focused on the new FQs moxifloxacin and gatifloxacin. Despite a lack of a comprehensive work comparing the activities of old and new classes of FQs in Mtb, what can be inferred from published results is that moxifloxacin and gatifloxacin are characterized by a higher activity against Mtb in vitro when compared to the old FQs ofloxacin and ciprofloxacin [77][78][79][80]. These new compounds are currently taken in consideration as anti-TB first-line drugs.…”

Section: Quinolones and Fluoroquinolonesmentioning

confidence: 99%

Role of quinolones and quinoxaline derivatives in the advancement of treatment of tuberculosis

Asif

2015

IJSW

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The need of new chemotherapeutic drugs to improve tuberculosis control and treatment particularly against multidrugresistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium. The atitubercular drugs are used in current chemotherapy have different chemical moieties. In this review, we provide an overview of the quinolone drugs as an antitubercular drug. Generally quinolone drugs are mainly used against many gram-positive and gram-negative bacterial infections including resistance strains also. Various quinolones are being used to control and treatment of tubercular infections including MDR, XDR and atypical Mycobacterium strains. Fluoroquinolones are an important quinolones, especially for strains that are resistant to first-line agents.

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In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis

Cited by 82 publications

References 20 publications

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

Role of fluoroquinolones in the treatment of tuberculosis

Role of quinolones and quinoxaline derivatives in the advancement of treatment of tuberculosis

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