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Boromycin Kills Mycobacterial Persisters without Detectable Resistance
#MMPMID26941723
Moreira W
; Aziz DB
; Dick T
Front Microbiol
2016[]; 7
(?): 199
PMID26941723
show ga
Boromycin is a boron-containing polyether macrolide antibiotic isolated from
Streptomyces antibioticus. It was shown to be active against Gram positive
bacteria and to act as an ionophore for potassium ions. The antibiotic is
ineffective against Gram negative bacteria where the outer membrane appears to
block access of the molecule to the cytoplasmic membrane. Here we asked whether
boromycin is active against Mycobacterium tuberculosis which, similar to Gram
negative bacteria, possesses an outer membrane. The results show that boromycin
is a potent inhibitor of mycobacterial growth (MIC50 = 80 nM) with strong
bactericidal activity against growing and non-growing drug tolerant persister
bacilli. Exposure to boromycin resulted in a rapid loss of membrane potential,
reduction of the intracellular ATP level and leakage of cytoplasmic protein.
Consistent with boromycin acting as a potassium ionophore, addition of KCl to the
medium blocked its antimycobacterial activity. In contrast to the potent
antimycobacterial activities of the polyether macrolide, its cytotoxicity and
haemolytic activity were low (CC50 = 30 ?M, HC50 = 40 ?M) with a selectivity
index of more than 300. Spontaneous resistant mutants could not be isolated
suggesting a mutation frequency of less than 10(-9)/CFU. Taken together, the
results suggests that targeting mycobacterial transmembrane ion gradients may be
an attractive chemotherapeutic intervention level to kill otherwise drug tolerant
persister bacilli, and to slow down the development of genetic antibiotic
resistance.
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