1: Antimicrob Agents Chemother 1996 May;40(5):1225-30
Effect of recombinant human gamma interferon on intracellular activities
of antibiotics against Listeria monocytogenes in the human macrophage cell
line THP-1.
Scorneaux B, Ouadrhiri Y, Anzalone G, Tulkens PM
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique
de Louvain, Brussels, Belgium.
Listeria monocytogenes is a facultative intracellular pathogen which enters
cells by endocytosis and reaches phagolysosomes from where it escapes and
multiplies in the cytosol of untreated cells. Exposure of macrophages to
gamma interferon (IFN-gamma) restricts L. monocytogenes to phagosomes and
prevents its intracellular multiplication. We have tested whether IFN-gamma
also modulates the susceptibility of L. monocytogenes to antibiotics. We
selected drugs from three different classes displaying marked properties
concerning their cellular accumulation and subcellular distribution, namely,
ampicillin (not accumulated by cells but present in cytosol), azithromycin
(largely accumulated by cells but mostly restricted to lysosomes), and
sparfloxacin (accumulated to a fair extent but detected only in cytosol).
We used a continuous line of myelomonocytic cells (THP-1 macrophages),
which display specific surface receptors for IFN-gamma, and examined the
activity of these antibiotics against L. monocytogenes Hly+ (virulent variant)
and L. monocytogenes Hly- (a nonvirulent variant defective in hemolysin
production). Untreated THP-1 and phorbol myristate acetate-differentiated
THP-1 were permissive for infection and multiplication of intracellular
L. monocytogenes Hly+ (virulent variant). All three antibiotics tested
were bactericidal against this Listeria strain when added to an extracellular
concentration of 10x their MIC. After preexposure of THP-1 to IFN-gamma,
L. monocytogenes Hly+ was still phagocytosed but no longer grew intracellularly.
The activity of ampicillin became almost undetectable (antagonistic effect),
and that of azithromycin was unchanged (additive effect with that of IFN-gamma),
whereas that of sparfloxacin was markedly enhanced (synergy). A similar
behavior (lack of bacterial growth, associated with a loss of activity
of ampicillin, an enhanced activity of sparfloxacin, and unchanged activity
of azithromycin) was observed in cells infected with L. monocytogenes Hly-.
This modulation of antibiotic activity, which we ascribe to the change
of subcellular localization of L. monocytogenes caused by IFN-gamma or
by the lack of virulence factor, could result from a change in bacterial
responsiveness to antibiotics, a modification of the drug activity, or
differences in drug bioavailabilities between cytosol and phagosomes.
PMID: 8723471, UI: 96300542