In vitro susceptibility of Mycobacterium avium complex to the new fluoroquinolone sparfloxacin (CI-978; AT-4140) and comparison with ciprofloxacin

Yajko, D M; Sanders, C A; Nassos, P S; Hadley, W K

doi:10.1128/aac.34.12.2442

Cited by 33 publications

(17 citation statements)

References 12 publications

(23 reference statements)

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“…Hydrophobic solutes can penetrate the barrier [1]. Antibiotics of the most hydrophobic types for example, are also the most effective drugs against mycobacteria [3,4].…”

Section: The Envelope Of Mycobacteriamentioning

confidence: 99%

“…Hydrophobic solutes can penetrate the barrier [1]. Antibiotics of the most hydrophobic types for example, are also the most effective drugs against mycobacteria [3,4].Considering the extreme rigidity and impermeability of the outer permeability barrier [5] of M. tuberculosis, it is a paradox that liquid cultures contain excessive amounts of soluble proteins which are much larger than the small solutes referred to above and do not have the hydrophobic properties that would make them pass. To explain the presence of the large quantities and wide repertoire of proteins in the culture filtrates, it is necessary to suggest that there is a mechanism for protein transport across the outer permeability barrier, maybe some kind Scand.…”

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confidence: 99%

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Liberation of Soluble Proteins from Live and Dead Mycobacterial Cells and the Implications for Pathogenicity of Tubercle Bacilli

Wiker¹

2001

Scand J Immunol

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Soluble proteins liberated from live M. tuberculosis are translocated through the cytoplasmic membrane to à periplasmic space'. For further export of proteins across the outer permeability barrier, it is necessary to postulate an excretion mechanism possibly involving some kind of porin. Observations of the repertoire of proteins in culture filtrates after liquid culture of M. tuberculosis show that a large repertoire of various kinds of proteins cross the outer permeability barrier of tubercle bacilli indicating that the excretion mechanism has a wide range of specificities for proteins. Culture filtrates of tubercle bacilli almost always contain both truly secreted proteins and cytoplasmatically-derived proteins. It is questionable whether cytoplasmic proteins can cross an intact cytoplasmic membrane. The simplest explanation for the appearance of cytoplasmic proteins in culture filtrates of tubercle bacilli would be that they are released after disintegration of the cytoplasmic membrane in dying or dead bacilli. Tubercle bacilli armed with secreted factors that may specifically inhibit innate and adaptive immune responses, excrete these from the periplasmic space of live bacilli. Unspecific in its character, the excretion mechanism also liberates proteins that are essential for building and maintaining the cell wall, thereby reducing the effectiveness of this process. This may be part of the explanation why M. tuberculosis and other pathogenic mycobacteria grow so slowly. Finally, it may be postulated that dormant or latent tubercle bacilli use their repertoire of secreted proteins to control their intracellular habitat and that bacterial cytoplasmic proteins would not be liberated from such bacilli. The consequence would be that only immune responses to secreted proteins would be effective for elimination of the dormant stage of infection. In a situation with active infection there will be considerable growth and turnover of bacilli with liberation of all kinds of immunogenic substances from the bacilli. In this situation immunity against cytoplasmic proteins would also be effective and immunity to cytoplasmic proteins should also be effective for control of the reactivation of latent disease because as soon as the bacilli start to grow there will also be a subpopulation of dead bacilli on the arena. THE ENVELOPE OF MYCOBACTERIACompared to many other bacterial genera, the outer permeability barrier of mycobacteria is extremely tight and particularly so for M. tuberculosis [1,2]. This is owing to the unusual structure of the mycobacterial cell wall which is highly impermeable to hydrophilic solutes. Hydrophobic solutes can penetrate the barrier [1]. Antibiotics of the most hydrophobic types for example, are also the most effective drugs against mycobacteria [3,4].Considering the extreme rigidity and impermeability of the outer permeability barrier [5] of M. tuberculosis, it is a paradox that liquid cultures contain excessive amounts of soluble proteins which are much larger than the small solutes referred to...

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“…Hydrophobic solutes can penetrate the barrier [1]. Antibiotics of the most hydrophobic types for example, are also the most effective drugs against mycobacteria [3,4].…”

Section: The Envelope Of Mycobacteriamentioning

confidence: 99%

mentioning

confidence: 99%

Liberation of Soluble Proteins from Live and Dead Mycobacterial Cells and the Implications for Pathogenicity of Tubercle Bacilli

Wiker¹

2001

Scand J Immunol

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“…The permeation ability of a lipophilic molecule is inversely related to the fluidity of the cell wall, which decreases as the length of fatty acids in the MA layer increases (51). Lipophilic drugs, such as fluoroquinolones or rifamycins, pass more easily through the lipid-rich cell wall and thus are more active (51,451).…”

Section: Why Are Mycobacteria So Innately Resistant To Antibiotics?mentioning

confidence: 99%

Bacterial Growth and Cell Division: a Mycobacterial Perspective

Hett

Rubín

2008

Microbiol Mol Biol Rev

342

293

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SUMMARY The genus Mycobacterium is best known for its two major pathogenic species, M. tuberculosis and M. leprae, the causative agents of two of the world's oldest diseases, tuberculosis and leprosy, respectively. M. tuberculosis kills approximately two million people each year and is thought to latently infect one-third of the world's population. One of the most remarkable features of the nonsporulating M. tuberculosis is its ability to remain dormant within an individual for decades before reactivating into active tuberculosis. Thus, control of cell division is a critical part of the disease. The mycobacterial cell wall has unique characteristics and is impermeable to a number of compounds, a feature in part responsible for inherent resistance to numerous drugs. The complexity of the cell wall represents a challenge to the organism, requiring specialized mechanisms to allow cell division to occur. Besides these mycobacterial specializations, all bacteria face some common challenges when they divide. First, they must maintain their normal architecture during and after cell division. In the case of mycobacteria, that means synthesizing the many layers of complex cell wall and maintaining their rod shape. Second, they need to coordinate synthesis and breakdown of cell wall components to maintain integrity throughout division. Finally, they need to regulate cell division in response to environmental stimuli. Here we discuss these challenges and the mechanisms that mycobacteria employ to meet them. Because these organisms are difficult to study, in many cases we extrapolate from information known for gram-negative bacteria or more closely related GC-rich gram-positive organisms.

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“…Its structure is similar to that of ciprofloxacin; however, it has two methyl groups in the piperazinyl ring and an additional fluorine atom at position 8, which, according to Schentag and Domagala (17), enhances its activity against grampositive organisms. Nakamura (13) and others (4,18,19) reported that sparfloxacin has a broad antibacterial spectrum that includes the pathogens mentioned above, which are not sufficiently susceptible to other quinolones. The present in vitro study was designed to establish (i) the antibacterial activity of sparfloxacin compared with those of other quinolones, (ii) the influence of changes in the pH of the culture medium, inoculum size, and Mg2+ concentration on the activity, (iii) the postaiitibiotic effect (PAE), and (iv) the in vitro mutational frequency rate to sparfloxacin resistance in a number of key pathogens.…”

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confidence: 99%

In vitro activity of sparfloxacin compared with those of five other quinolones

Cantón¹,

Pemán²,

Jimenez³

et al. 1992

Antimicrob Agents Chemother

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The in vitro activity of sparfloxacin, a new difluorinated quinolone, was evaluated against 857 gram-positive and gram-negative clinical isolates and compared with those of ciprofloxacin, norfloxacin, ofloxacin, fleroxacin, and lomefloxacin. The MIC of sparfloxacin for 90%o of the members of the family Enterobacteriaceae tested was 0.5 ig/ml (range, 0.06 to 4.0 uig/mI); only for members of the genera Serratia,-Citrobacter, and Providencia were MICs above 1 ug/mL. Some 90% of Pseudomonas aeruginosa isolates were inhibited by 8 ,ug of the drug per ml. The MICs for 90% of Staphylococcus spp. and Enterococcus faecalis were 0.12 and 2 ,ug/ml, respectively. All (100%) Streptococcus pneumoniae strains were inhibited by 0.5 ,ug/ml. The inoculum size had little effect on either the MIC or the MBC of sparfloxacin. An increase in the magnesium concentration from 1.1 to 8.4 mM increased the MIC between 2 and 10 times, depending on the genus tested. Sparfloxacin was less active at pH 5. The antibacterial activity of sparfloxacin against gram-positive bacteria was generally higher than those of the quinolones with which it was compared; against Streptococcus pneumoniae, sparfloxacin was four-and eightfold more active than ofloxacin and ciprofloxacin, respectively. The activity of sparfloxacin against gram-negative rods was generally comparable to that of ciprofloxacin except against Enterobacter and Acinetobacter spp., Pseudomonas cepacia, Xanthomonas maltophiia, and Alcaligenes and Flavobacterium spp., against which sparfloxacin was the most active quinolone.In 1962 Lesher et al. (9) synthesized nalidixic acid, the first urinary tract antiseptic of the quinolone group to be used clinically. In the last decade, more than 200 quinolone derivatives have been synthesized, some with a broad spectrum and improved pharmacology. Nevertheless, some important pathogens such as enterococci, streptococci, Mycobacterium spp., Chlamydia spp., and Mycoplasma spp. are not sufficiently susceptible to some quinolones. Sparfloxacin (AT-4140; Rp 64206), 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, is a new difluorinated quinolone. Its structure is similar to that of ciprofloxacin; however, it has two methyl groups in the piperazinyl ring and an additional fluorine atom at position 8, which, according to Schentag and Domagala (17), enhances its activity against grampositive organisms. Nakamura (13) and others (4,18,19) reported that sparfloxacin has a broad antibacterial spectrum that includes the pathogens mentioned above, which are not sufficiently susceptible to other quinolones. The present in vitro study was designed to establish (i) the antibacterial activity of sparfloxacin compared with those of other quinolones, (ii) the influence of changes in the pH of the culture medium, inoculum size, and Mg2+ concentration on the activity, (iii) the postaiitibiotic effect (PAE), and (iv) the in vitro mutational frequency rate to sparfloxacin resistance in a number of key pathog...

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In vitro susceptibility of Mycobacterium avium complex to the new fluoroquinolone sparfloxacin (CI-978; AT-4140) and comparison with ciprofloxacin

Cited by 33 publications

References 12 publications

Liberation of Soluble Proteins from Live and Dead Mycobacterial Cells and the Implications for Pathogenicity of Tubercle Bacilli

Liberation of Soluble Proteins from Live and Dead Mycobacterial Cells and the Implications for Pathogenicity of Tubercle Bacilli

Bacterial Growth and Cell Division: a Mycobacterial Perspective

In vitro activity of sparfloxacin compared with those of five other quinolones

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