Effect of Lipophilicity at N-1 on Activity of Fluoroquinolones against Mycobacteria

Renau, Thomas E.; Sanchez, Joseph P.; Shapiro, Martin A.; Dever, J A; Gracheck, Stephen J.; Domagala, John M.

doi:10.1021/jm00015a021

Cited by 44 publications

(38 citation statements)

References 3 publications

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“…This is consistent with the previous observation that the activities of fluoroquinolones against mycobacteria increase with the hydrophobicity of the drugs (17) and may indicate a preference of the fluoroquinolones for direct diffusion through the lipid membranes of mycobacteria. On the other hand, increasing lipophilicity of the substituent at position N-1 did not correlate with increased potency against mycobacteria (46). We observed a fourfold increase in the resistance of the porin triple mutant ML16 to sparfloxacin and moxifloxacin compared to wt M. smegmatis (Table 1).…”

Section: Resultsmentioning

confidence: 69%

Role of Porins for Uptake of Antibiotics by Mycobacterium smegmatis

Danilchanka

Pavlenok

Niederweis

2008

Antimicrob Agents Chemother

117

104

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The outer membrane of mycobacteria presents an effective permeability barrier for many antibiotics. Transport pathways across this membrane are unknown for most drugs. Here, we examined which antibiotics utilize the porin pathway across the outer membrane of the model organism Mycobacterium smegmatis. Deletion of the porins MspA and MspC drastically increased the resistance of M. smegmatis ML10 to ␤-lactam antibiotics, while its ␤-lactamase activity remained unchanged. These results are consistent with the ninefoldreduced outer membrane permeability of the M. smegmatis porin mutants for cephaloridine and strongly indicate that ␤-lactam antibiotics rely on the porin pathway. The porin mutant ML10 accumulated less chloramphenicol and norfloxacin and was less susceptible to these antibiotics than wild-type M. smegmatis. These results demonstrated that small and hydrophilic antibiotics use the Msp porins for entering the cell. In contrast to norfloxacin, the hydrophobic moxifloxacin was 32-fold more effective in inhibiting the growth of M. smegmatis, presumably because it was able to diffuse through the lipid membrane. Structural models indicated that erythromycin, kanamycin, and vancomycin are too large to move through the MspA channel. This study presents the first experimental evidence that hydrophilic fluoroquinolones and chloramphenicol diffuse through porins in mycobacteria. Thus, mutations resulting in less efficient porins or lower porin expression levels are likely to represent a mechanism for the opportunistic pathogens M. avium, M. chelonae, and M. fortuitum, which have Msp-like porins, to acquire resistance to fluoroquinolones.

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Section: Resultsmentioning

confidence: 69%

Role of Porins for Uptake of Antibiotics by Mycobacterium smegmatis

Danilchanka

Pavlenok

Niederweis

2008

Antimicrob Agents Chemother

117

104

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“…These results suggested that 2,8-diazabicyclo[4.3.0]nonanyl, 3-aminomethylpyrrolidinyl, and 4,4-dialkyl-3-aminopyrrolidinyl groups were more effective for the activities against both MAC and M. tuberculosis than the piperazinyl group. There have been several reports demonstrating the SARs between antimycobacterial activity and the substituents of the N-1 and C-8 position of the 4-quinolone nucleus (7,11,14,23,24). In practice, a combination of the basic substituents and variations of the 4-quinolone nucleus leads to subtle changes in the intrinsic antibacterial activity.…”

Section: Discussionmentioning

confidence: 99%

Antimycobacterial Activities of Novel Levofloxacin Analogues

Kawakami

Namba

Tanaka

et al. 2000

Antimicrob Agents Chemother

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In order to investigate structure-activity relationships between antimycobacterial activities and basic substituents at the C-10 position of levofloxacin (LVFX), we synthesized a series of pyridobenzoxazine derivatives by replacement of the N-methylpiperazinyl group of LVFX with various basic substituents. A compound with a 3-aminopyrrolidinyl group had one-half the activity of LVFX against Mycobacterium avium, M. intracellulare, and M. tuberculosis. Mono-and dimethylation of the 3-amino moiety of the pyrrolidinyl group increased the activities against M. avium and M. intracellulare but not those against M. tuberculosis. On the other hand, dialkylation at the C-4 position of the 3-aminopyrrolidinyl group enhanced the activities against M. avium, M. intracellulare, and M. tuberculosis. Thus, introduction of an N-alkyl or a C-alkyl group(s) into the 3-aminopyrrolidinyl group may contribute to an increase in potency against M. avium, M. intracellulare, and/or M. tuberculosis, probably through elevation of the lipophilicity. However, among the compounds synthesized, compound VII, which was a 2,8-diazabicyclo[4.3.0]nonanyl derivative with relatively low lipophilicity, showed the most potent activity against mycobacterial species: the activity was 4-to 32-fold more potent than that of LVFX and two to four times as potent as that of gatifloxacin. These results suggested that an increase in the lipophilicity of LVFX analogues in part contributed to enhancement of antimycobacterial activities but that lipophilicity of the compound was not a critical factor affecting the potency.During the past decade, an increase in the number of patients with tuberculosis has been one of the most serious health problems in many countries (2, 27). In particular, the now pandemic combination of tuberculosis with human immunodeficiency syndrome (2,3,20) and the appearance of multidrug-resistant Mycobacterium tuberculosis (6, 10, 32) have aggravated attempts to treat these patients. In addition, the number of patients infected with Mycobacterium avium-M. intracellulare complex (MAC) is on the increase (5, 9). However, an effective therapy for MAC infection has not yet been established. Given these observations, the development of effective drugs for the mycobacterial infections described above has been keenly desired.Recently, new quinolone antibacterial agents have been developed and marketed and are widely used clinically. They have potent and broad activities against both gram-negative and gram-positive pathogens. These agents also have been evaluated and shown to have potent activities against certain types of mycobacterial species in in vitro tests and in experimental animals (ofloxacin [26,29,31] LVFX is a representative new quinolone which is characterized by its potency, safety, and good pharmacokinetic profiles in humans. This agent has a unique pyridobenzoxazine structure. In the previous paper, members of our group reported the synthesis of pyridobenzoxazines bearing a series of 3-aminopyrrolidinyl substituents at the C-10 posito...

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“…IR spectra (KBr pellets) were recorded with a Perkin-Elmer-1700 spectro photo meter. 1 H NMR and 13 C NMR spectra were measured on avance Bruker-300 MHz spectrometer. Mass spectrum was recorded on Varian 300-MS spectrometer and melting points were recorded on a Polmon MP96.…”

Section: Instrumentationmentioning

confidence: 99%

“…Fluoroquinolones are compounds which posses a wide variety of therapeutically interesting antibacterial activity against various Gram-positive and Gram-negative bacteria [1,2]. The board spectrum of antibiotic activity of these compounds is mainly due to the presence of a fluorine atom at position C-6, chemical modification at position C-7 (piperazine moiety) of fluroquinolones ring system [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%