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Antimicrobial Agents and Chemotherapy, June 1999, p. 1459-1462, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Outer Membrane Permeability Barrier in Escherichia
coli Mutants That Are Defective in the Late Acyltransferases of
Lipid A Biosynthesis
Martti
Vaara1,2,3,* and
Marjatta
Nurminen1,3
Division of Bacteriology and Immunology,
Helsinki University Central Hospital,1
Department of Bacteriology, University of
Helsinki,2 and Department of
Bacteriology, National Public Health
Institute,3 Helsinki, Finland
Received 13 October 1998/Returned for modification 28 January
1999/Accepted 28 March 1999
 |
ABSTRACT |
The tight packing of six fatty acids in the lipid A constituent of
lipopolysaccharide (LPS) has been proposed to contribute to the
unusually low permeability of the outer membrane of gram-negative enteric bacteria to hydrophobic antibiotics. Here it is shown that the
Escherichia coli msbB mutant, which elaborates defective, penta-acylated lipid A, is practically as resistant to a representative set of hydrophobic solutes (rifampin, fusidic acid, erythromycin, clindamycin, and azithromycin) as the parent-type control strain. The
susceptibility index, i.e., the approximate ratio between the MIC for
the msbB mutant and that for the parent-type control, was
maximally 2.7-fold. In comparison, the rfa mutant defective in the deep core oligosaccharide part of LPS displayed indices ranging
from 20 to 64. The lpxA and lpxD lipid A
mutants had indices higher than 512. Furthermore, the msbB
mutant was resistant to glycopeptides (vancomycin, teicoplanin),
whereas the rfa, lpxA, and lpxD
mutants were susceptible. The msbB htrB double mutant, which elaborates even-more-defective, partially tetra-acylated lipid A,
was still less susceptible than the rfa mutant. These findings indicate that hexa-acylated lipid A is not a prerequisite for
the normal function of the outer membrane permeability barrier.
| |
INTRODUCTION |
The outer membrane (OM) of
gram-negative bacteria acts as an effective permeability barrier
against external noxious agents, and lipopolysaccharide (LPS) is the
key molecule for this function (9). In the OM of
gram-negative enteric bacteria, the LPS molecules occupy the outer
leaflet of the OM and leave no space for glycerophospholipids, which
thus occupy the inner leaflet. The LPS monolayer is a highly ordered
quasicrystalline structure with very low fluidity (7-9, 16). Such a structure may not allow rapid diffusion of
hydrophobic solutes, and hydrophobic probe molecules have indeed been
shown to partition very poorly into the hydrophobic interior portion of
isolated LPS (8, 17).
Escherichia coli lpxA, lpxC, and
lpxD mutants have profound defects in the biosynthesis of
the lipid A part of the LPS and are extremely susceptible to
hydrophobic antibiotics (10, 14, 18, 19). Since they
synthesize greatly reduced amounts of LPS, the most probable
explanation for their supersusceptibility is simply the lack of a
continuous LPS layer in the outer leaflet and the resultant
compensatory presence of glycerophospholipids in this leaflet (14,
16). This creates glycerophospholipid bilayers or patches in the
OM that allow the diffusion of hydrophobic solutes. Such patches have
been demonstrated in another group of antibiotic-supersusceptible
mutants, the deep rough mutants that elaborate the very truncated LPS
inner core (8, 9). The lpx mutants are also
susceptible to large peptide antibiotics. Since these hydrophilic
peptides cannot penetrate the OM of the lipid A mutants through the
glycerophospholipid patches, they probably enter via transient ruptures
(14, 16).
The highly ordered structure of the LPS layer is probably due to tight
lateral interaction of the LPS molecules, mediated by divalent cations
that bridge the anionic LPS molecules (8, 9). Contributing
factors could also include the rigidifying effects of (i) the inner
core oligosaccharide domain as well as (ii) the tightly packed set of
six fatty acids in lipid A (four linked to the nonreducing glucosamine
residue GlcN' [8, 9]). Interestingly, lipid A mutants
have recently been described that are defective in the transfer of the
last two fatty acids (late acylations) to the nascent lipid A (1,
2, 4, 5, 11). In the present study we show that an
msbB mutant that produces penta-acylated lipid A (only three
fatty acids linked to GlcN' [Fig. 1]) has an intact permeability
barrier against both hydrophobic antibiotics and large glycopeptides.
These findings indicate that hexa-acylation of lipid A, which results
in very tight fatty acid packing of GlcN', is not crucial to the
function of the barrier. Furthermore, we show that the
even-more-defective mutant (msbB htrB) which produces a
partially tetra-acylated lipid A still possesses an OM permeability
barrier that is less defective than those of the deep rough mutants and
the lpx mutants.
| |
MATERIALS AND METHODS |
Strains.
E. coli strains defective in late acylations
of lipid A were the knockout mutants MLK53
(htrB1::Tn10), MLK1067
(msbB::
cam), and MLK986
(htrB1::Tn10
msbB::cam) (4), obtained from
Chris Raetz (Durham, N.C.). MLK1067 lacks the msbB-encoded
(Kdo)2-(lauroyl)-lipidIVA myristoyltransferase and produces penta-acylated lipid A that is devoid
of the myristic acid residue (Fig. 1);
only extremely small amounts of hexa-acylated lipid A can be detected
(2). This lack has been verified by a report on another
msbB mutant allele of E. coli (11).
The msbB gene is not essential for bacterial growth, and
MLK1067 grows well even at 42°C (4).
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FIG. 1.
Structures of the lipid A part of the LPS of wild-type
E. coli (A) and the msbB mutant of E. coli, which lacks the myristic acid (C14) residue (B). The
msbB htrB double mutant also lacks part of the lauric acid
residue (C12) (see text). Acylations catalyzed by MsbB and HtrB are
shown in panel A.
|
|
MLK53 and MLK986 are thermosensitive and grow well at 30°C but poorly
at 37°C (4). They lack the htrB-encoded
(Kdo)2-lipidIVA lauroyltransferase
(1). At 30°C, MLK53 produces a mixture of tetra-, penta-,
and hexa-acylated lipid A, apparently because the
msbB-encoded acyltransferase is able to compensate partially for the loss of htrB (2). The double mutant
MLK986 that lacks both htrB and msbB elaborates
at 30°C lipid A with a significant fraction of the tetra-acylated
form (2). Due to the compensatory activity of still other
acyltransferases, part of the lipid A formed at 30°C by the double
mutant is penta-acylated.
The other lipid A mutants were SM101 (lpxA2
[3]) and CDH23-213 (lpxD [the gene
formerly known as omsA, firA, and
ssc] [19]), both of which are
thermosensitive. SM101 grows well at 28°C but not at 37°C;
CDH23-213 grows well at 20 and 37°C but not at 42°C. Detailed
phenotypic analyses of these strains as well as their isogenic control
strains SM105 (lpxA+) and CDH23-210
(lpxD+) have been published previously (14,
18, 19).
The strain with a defective LPS inner core was E. coli D21f2
(rfa); it elaborates Re-type (heptoseless) LPS and has
previously been well characterized (14). IH3080 (O18:K1:H7
[15]) was the smooth, encapsulated E. coli
strain used. Micrococcus luteus ATCC 9341 was the
representative antibiotic-susceptible gram-positive bacterium.
Susceptibility determinations.
Susceptibilities were
measured by using E-test strips (AB Biodisk, Solna, Sweden) according
to the methodology recommended by the manufacturer, with an incubation
time of 18 h. The test was performed on Luria-Bertani agar plates
(10 g of tryptone; Difco Laboratories, Detroit, Mich.) with 5 g of
yeast extract (Oxoid, Columbia, Md.), 5 g of NaCl, and 15 g
of agar (pH 7.2). The inoculum for the test consisted of Luria-Bertani
agar-grown bacteria in their early stationary growth phase. The E test
can be used to reliably determine MICs for supersusceptible
enterobacterial mutants (15).
| |
RESULTS AND DISCUSSION |
The OM permeability barrier to hydrophobic antibiotics.
It has
been reported previously, by using an insensitive agar streak method,
that the htrB and msbB mutants show no increased susceptibility to rifampin (4). This interesting finding
needs verification and further analysis. Since some mutants
supersusceptible to hydrophobic antibiotics display no altered
susceptibility to rifampin (12), a broader range of
hydrophobic antibiotics was chosen for study of the permeability
barrier. These included dibasic (azithromycin), monobasic (erythromycin
and clindamycin), monoanionic (fusidic acid), and zwitterionic
(rifampin) antibiotics.
The MICs of all those antibiotics for the msbB mutant
MLK1067 were almost as high as those for the reference E. coli K-12 strain SM105 as well as for strain IH3080 (Fig.
2). The susceptibility index, i.e., the
approximate ratio between the MIC for strain SM105 and that for the
mutant MLK1067, ranged between 2.7 and 0.7. Temperature had little
effect on the MICs; MLK1067 remained resistant even at 42°C (data not
shown).
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|
FIG. 2.
MICs of rifampin (A), fusidic acid (B), erythromycin
(C), clindamycin (D), azithromycin (E), and vancomycin (F) for E. coli mutants defective in the synthesis of LPS core
oligosaccharide or lipid A as well as for their parent-type controls.
Susceptibility determinations were performed at 28°C ( ) and 37°C
( ). Lanes: 1, strain IH3080 (smooth, encapsulated control); 2, strain SM105 (K-12 wild-type control); 3, strain MLK1067
(msbB); 4, strain MLK53 (htrB); 5, strain MLK986
(msbB htrB); 6, strain D21f2 (rfa, LPS chemotype
Re); 7, strain CDH23-213 (lpxD); and 8, strain SM101
(lpxA). Susceptibility of a gram-positive bacterium,
M. luteus ATCC 9341 (lanes 9), is shown for comparison.
|
|
The lack of supersusceptibility in MLK1067 indicates that hexa-acylated
lipid A is not a prerequisite for the normal function of the OM
permeability barrier. This function is severely impaired in the deep
rough strain D21f2, which displayed susceptibility indices ranging from
20 to 64 (Fig. 2); yet its lipid A is not defective, in contrast to
that of the msbB mutant (Fig. 1). The MICs for strain D21f2
were comparable to those previously determined for the Re-type strains
of Salmonella typhimurium and Salmonella minnesota but still higher than those for the lipid A mutants SM101 (lpxA) and CDH-213 (lpxD), which displayed
susceptibility indices higher than 512 (Fig. 2).
The msbB htrB double mutant (MLK986) was consistently more
susceptible than the wild-type control and MLK1067 but less susceptible than the deep rough strain with the Re-type LPS (D21f2). The
htrB single mutant MLK53 with the msbB-mediated
compensatory mechanism working at 30°C (see above) displayed no
increase in susceptibility.
The finding of the supersusceptibility of MLK986 is novel but
compatible with the report that the amount of LPS is decreased in the
OM of the htrB mutant at 42°C (6), the
temperature at which the msbB-mediated compensatory
mechanism is abolished (2). This decrease apparently results
in the observed (6) increase in glycerophospholipids that
creates gates for hydrophobic diffusion, i.e., phospholipid bilayer
patches (see above).
The OM permeability barrier to glycopeptides.
Vancomycin and
teicoplanin are hydrophilic glycopeptides and are effectively excluded
by the intact enterobacterial OM. As the lpxA and
lpxD mutants are very susceptible to vancomycin, their OM is
probably fragile and transiently ruptured (14). Another
indication of such ruptures is that both mutants leak remarkable
amounts of their periplasmic proteins into the growth medium.
As shown in Fig. 2, MLK1067 was resistant to vancomycin. Accordingly,
it can be concluded that its OM is not fragile. MLK1067 remained
resistant to vancomycin even at 42°C (data not shown). In contrast,
the MIC of vancomycin for the double mutant MLK986 was rather low,
indicating a tendency for the formation of ruptures in the OM.
Teicoplanin appeared to be a less-sensitive probe than vancomycin (data
not shown).
General conclusions.
This report shows that hexa-acylation of
lipid A, which results in very tight fatty acid packing of GlcN', is
not a prerequisite for normal function of the OM permeability barrier.
Surprisingly, penta-acylated lipid A, which lacks the myristic acid
residue of the nonreducing glucosamine, can completely replace the
hexa-acyl form in this function. The very tight fatty acid packing of
lipid A, and especially of its GlcN', could contribute to the rigidity of the hydrophobic interior of LPS monolayer and thus to the relatively poor diffusion of hydrophobic solutes through this layer (8, 9). Tight packing of fatty acids, such as that in the glycolipids of the extreme thermophilic eubacterium Thermus, is expected
to strengthen the hydrophobic and van der Waal's interactions between neighboring molecules (8). However, despite the loss of one fatty acid residue, the remaining penta-acylated lipid A remains extremely richly acylated, and therefore the above-mentioned finding cannot be seen as a serious challenge to the validity of the theory. The study of the tetra-acylated lipid A would be interesting, but the
pleiotropic changes in the structure of the OM of the htrB
msbB mutant (see above) as well as the compensatory effects of
additional fatty acid transferases would make interpretation of the
results impossible. Therefore, hydrophobic permeability measurement
techniques that employ artificial LPS mono- or bilayers and synthetic
or purified lipid A and LPS derivatives are needed.
msbB mutants such as MLK1067 are becoming increasingly
valuable in research on gram-negative bacterial infections
(20). They grow at the same rate as their wild-type parents
and are less virulent and much less active in eliciting macrophage
responses. Because these strains can provide new insights into
endotoxin research and novel opportunities for vaccine development,
they should be characterized in detail. As shown in the present study, OM permeability barrier function, one of the main functions of LPS, is
unimpaired in the msbB mutant.
| |
ACKNOWLEDGMENTS |
The excellent technical assistance of Raija Lahdenperä and
Sirkka-Liisa Skogberg is gratefully acknowledged.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Bacteriology, University of Helsinki, Haartmaninkatu 3, 00014 Helsinki, Finland. Phone: 358-9-1912-6302. Fax: 358-9-1912-6382. E-mail: Martti.Vaara{at}Helsinki.fi.
| |
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Antimicrobial Agents and Chemotherapy, June 1999, p. 1459-1462, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Top
Abstract
Introduction
