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Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria
1Public Health Research Institute, New York, New York 10016, USA.
Abstract:
Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated. To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations. Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring. When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells. For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs. Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not. With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.
Insights
Mutant prevention concentration (MPC) offers insights into antibiotic potency beyond the minimum inhibitory concentration (MIC). This study found MPC better predicts resistance selection in Mycobacterium smegmatis than MIC alone.
Area of Science:
- Microbiology
- Pharmacology
- Antibiotic Resistance
Background:
- Mutant prevention concentration (MPC) is a proposed metric for antibiotic potency, evaluating the capacity to inhibit the emergence of resistant bacterial mutants.
- The minimum inhibitory concentration (MIC) is the standard measure, but its ability to predict resistance selection is sometimes limited.
Purpose of the Study:
- To assess if MPC provides unique information on fluoroquinolone potency compared to MIC.
- To investigate the correlation between MPC and MIC in selecting resistant mutants of Mycobacterium smegmatis.
Main Methods:
- Testing 18 fluoroquinolones against Mycobacterium smegmatis wild-type and resistant strains.
- Evaluating the ability of fluoroquinolones to inhibit growth and prevent selection of resistant mutants.
- Analyzing the impact of structural modifications at the C-8 and C-7 positions of fluoroquinolones on MPC and MIC values.
Main Results:
- Both MPC and MIC were influenced by modifications at the C-8 and C-7 positions of the fluoroquinolones.
- For C-8-methoxy and C-8-hydrogen derivatives, the MIC of resistant mutants correlated better with MPC than did the MIC of wild-type cells.
- For C-8-fluorine derivatives, MICs for both mutant and wild-type strains correlated well with MPC.
Conclusions:
- MPC provides additional information on antibiotic potency regarding resistance selection that MIC may not fully capture.
- While MIC for wild-type cells can sometimes reflect resistance selection potential, it is not always sufficient.
- The most potent fluoroquinolones in this series featured a C-8-methoxy group and a small C-7 ring substituent.