scholarly journals Efflux Pumps of Burkholderia thailandensis Control the Permeability Barrier of the Outer Membrane

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Ganesh Krishnamoorthy ◽  
Jon W. Weeks ◽  
Zhen Zhang ◽  
Courtney E. Chandler ◽  
Haotian Xue ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Lipid A ◽  
Efflux Pumps ◽  
Underlying Mechanism ◽  
Antibacterial Activities ◽  
Permeability Barrier ◽  
Contributing Factors ◽  
Burkholderia Thailandensis ◽  
Content Type ◽  
Active Efflux

ABSTRACT Burkholderia comprises species that are significant biothreat agents and common contaminants of pharmaceutical production facilities. Their extreme antibiotic resistance affects all classes of antibiotics, including polycationic polymyxins and aminoglycosides. The major underlying mechanism is the presence of two permeability barriers, the outer membrane with modified lipid A moieties and active drug efflux pumps. The two barriers are thought to be mechanistically independent and act synergistically to reduce the intracellular concentrations of antibiotics. In this study, we analyzed the interplay between active efflux pumps and the permeability barrier of the outer membrane in Burkholderia thailandensis. We found that three efflux pumps, AmrAB-OprA, BpeEF-OprC, and BpeAB-OprB, of B. thailandensis are expressed under standard laboratory conditions and provide protection against multiple antibiotics, including polycationic polymyxins. Our results further suggest that the inactivation of AmrAB-OprA or BpeAB-OprB potentiates the antibacterial activities of antibiotics not only by reducing their efflux, but also by increasing their uptake into cells. Mass spectrometry analyses showed that in efflux-deficient B. thailandensis cells, lipid A species modified with 4-amino-4-deoxy-l-aminoarabinose are significantly less abundant than in the parent strain. Taken together, our results suggest that changes in the outer membrane permeability due to alterations in lipid A structure could be contributing factors in antibiotic hypersusceptibilities of B. thailandensis cells lacking AmrAB-OprA and BpeAB-OprB efflux pumps.

scholarly journals Substrate Specificities and Efflux Efficiencies of RND Efflux Pumps ofAcinetobacter baumannii

2018 ◽  
Vol 200 (13) ◽  
pp. e00049-18 ◽  
Author(s):  
Inga V. Leus ◽  
Jon W. Weeks ◽  
Vincent Bonifay ◽  
Lauren Smith ◽  
Sophie Richardson ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Antibacterial Activities ◽  
Permeability Barrier ◽  
Bacterial Cells ◽  
Content Type ◽  
Active Efflux ◽  
Rnd Efflux Pumps ◽  
The Impact

ABSTRACTAntibiotic-resistantAcinetobacter baumanniicauses infections that are extremely difficult to treat. A significant role in these resistance profiles is attributed to multidrug efflux pumps, especially those belonging to the resistance-nodulation-cell division (RND) superfamily of transporters. In this study, we analyzed functions and properties of RND efflux pumps inA. baumanniiATCC 17978. This strain is susceptible to antibiotics and does not contain mutations that are commonly selected upon exposure to high concentrations of antibiotics. We constructed derivatives of ATCC 17978 lacking chromosomally encoded RND pumps and complemented these strains by the plasmid-borne genes. We analyzed the substrate selectivities and efficiencies of the individual pumps in the context of native outer membranes and their hyperporinated variants. Our results show that inactivation of AdeIJK provides the strongest potentiation of antibiotic activities, whereas inactivation of AdeFGH triggers the overexpression of AdeAB. The plasmid-borne overproduction complements the hypersusceptible phenotypes of the efflux deletion mutants to the levels of the parental ATCC 17978. Only a few antibiotics strongly benefitted from the overproduction of efflux pumps and antibacterial activities of some of those depended on the synergistic interaction with the low permeability barrier of the outer membrane. Either overproduction or inactivation of efflux pumps change dramatically the lipidome of ATCC 17978. We conclude that efflux pumps ofA. baumanniiare tightly integrated into physiology of this bacterium and that clinical levels of antibiotic resistance inA. baumanniiisolates are unlikely to be reached solely due to the overproduction of RND efflux pumps.IMPORTANCERND-type efflux pumps are important contributors in development of clinical antibiotic resistance inA. baumannii. However, their specific roles and the extent of contribution to antibiotic resistance remain unclear. We analyzed antibacterial activities of antibiotics in strains with different permeability barriers and found that the role of active efflux in antibiotic resistance ofA. baumanniiis limited to a few select antibiotics. Our results further show that the impact of efflux pump overproduction on antibiotic susceptibility is significantly lower than the previously reported for clinical isolates. Additional mechanisms of resistance, in particular those that improve the permeability barriers of bacterial cells and act synergistically with active efflux pumps are likely involved in antibiotic resistance of clinicalA. baumanniiisolates.

scholarly journals Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Ganesh Krishnamoorthy ◽  
Inga V. Leus ◽  
Jon W. Weeks ◽  
David Wolloscheck ◽  
Valentin V. Rybenkov ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Efflux Pumps ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Active Efflux ◽  
Membrane Barrier ◽  
Biological Determinants ◽  
Resistant Strains

ABSTRACT Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens. IMPORTANCE Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of P. aeruginosa, A. baumannii, Burkholderia thailandensis, and B. cepacia. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery. IMPORTANCE Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of P. aeruginosa, A. baumannii, Burkholderia thailandensis, and B. cepacia. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.

scholarly journals Bordetella pertussis Lipid A Glucosamine Modification Confers Resistance to Cationic Antimicrobial Peptides and Increases Resistance to Outer Membrane Perturbation

2014 ◽  
Vol 58 (8) ◽  
pp. 4931-4934 ◽  
Author(s):  
Nita R. Shah ◽  
Robert E. W. Hancock ◽  
Rachel C. Fernandez
Keyword(s):  
Immune System ◽  
Antimicrobial Peptides ◽  
Outer Membrane ◽  
Bordetella Pertussis ◽  
Lipid A ◽  
Whooping Cough ◽  
Human Immune System ◽  
Cationic Antimicrobial Peptides ◽  
Content Type ◽  
Membrane Perturbation

ABSTRACTBordetella pertussis, the causative agent of whooping cough, has many strategies for evading the human immune system. Lipopolysaccharide (LPS) is an important Gram-negative bacterial surface structure that activates the immune system via Toll-like receptor 4 and enables susceptibility to cationic antimicrobial peptides (CAMPs). We show modification of the lipid A region of LPS with glucosamine increased resistance to numerous CAMPs, including LL-37. Furthermore, we demonstrate that this glucosamine modification increased resistance to outer membrane perturbation.

scholarly journals Outer Membrane Lipid Secretion and the Innate Immune Response to Gram-Negative Bacteria

2020 ◽  
Vol 88 (7) ◽  
Author(s):  
Nicole P. Giordano ◽  
Melina B. Cian ◽  
Zachary D. Dalebroux
Keyword(s):  
Outer Membrane ◽  
Mammalian Cells ◽  
Lipid A ◽  
Membrane Lipid ◽  
Membrane Curvature ◽  
Host Immunity ◽  
Host Recognition ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Gram Negative

ABSTRACT The outer membrane (OM) of Gram-negative bacteria is an asymmetric lipid bilayer that consists of inner leaflet phospholipids and outer leaflet lipopolysaccharides (LPS). The asymmetric character and unique biochemistry of LPS molecules contribute to the OM’s ability to function as a molecular permeability barrier that protects the bacterium against hazards in the environment. Assembly and regulation of the OM have been extensively studied for understanding mechanisms of antibiotic resistance and bacterial defense against host immunity; however, there is little knowledge on how Gram-negative bacteria release their OMs into their environment to manipulate their hosts. Discoveries in bacterial lipid trafficking, OM lipid homeostasis, and host recognition of microbial patterns have shed new light on how microbes secrete OM vesicles (OMVs) to influence inflammation, cell death, and disease pathogenesis. Pathogens release OMVs that contain phospholipids, like cardiolipins, and components of LPS molecules, like lipid A endotoxins. These multiacylated lipid amphiphiles are molecular patterns that are differentially detected by host receptors like the Toll-like receptor 4/myeloid differentiation factor 2 complex (TLR4/MD-2), mouse caspase-11, and human caspases 4 and 5. We discuss how lipid ligands on OMVs engage these pattern recognition receptors on the membranes and in the cytosol of mammalian cells. We then detail how bacteria regulate OM lipid asymmetry, negative membrane curvature, and the phospholipid-to-LPS ratio to control OMV formation. The goal is to highlight intersections between OM lipid regulation and host immunity and to provide working models for how bacterial lipids influence vesicle formation.

scholarly journals Outer Membrane Permeability Barrier in Escherichia coli Mutants That Are Defective in the Late Acyltransferases of Lipid A Biosynthesis

1999 ◽  
Vol 43 (6) ◽  
pp. 1459-1462 ◽  
Author(s):  
Martti Vaara ◽  
Marjatta Nurminen
Keyword(s):  
Escherichia Coli ◽  
Membrane Permeability ◽  
Outer Membrane ◽  
Lipid A ◽  
Enteric Bacteria ◽  
Normal Function ◽  
Permeability Barrier ◽  
Core Oligosaccharide ◽  
Hydrophobic Solutes ◽  
Outer Membrane Permeability

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 theEscherichia 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 msbBmutant was resistant to glycopeptides (vancomycin, teicoplanin), whereas the rfa, lpxA, and lpxDmutants 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.

scholarly journals Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

2016 ◽  
Vol 60 (4) ◽  
pp. 2373-2382 ◽  
Author(s):  
François Guérin ◽  
Claire Lallement ◽  
Christophe Isnard ◽  
Anne Dhalluin ◽  
Vincent Cattoir ◽  
...  
Keyword(s):  
Cell Division ◽  
Antimicrobial Resistance ◽  
Galleria Mellonella ◽  
Acquired Resistance ◽  
Enterobacter Cloacae ◽  
Efflux Pumps ◽  
Wild Type ◽  
Content Type ◽  
Active Efflux

ABSTRACTIn Gram-negative bacteria, the active efflux is an important mechanism of antimicrobial resistance, but little is known about theEnterobacter cloacaecomplex (ECC). It is mediated primarily by pumps belonging to the RND (resistance-nodulation-cell division) family, and only AcrB, part of the AcrAB-TolC tripartite system, was characterized in ECC. However, detailed genome sequence analysis of the strainE. cloacaesubsp.cloacaeATCC 13047 revealed to us that 10 other genes putatively coded for RND-type transporters. We then characterized the role of all of these candidates by construction of corresponding deletion mutants, which were tested for their antimicrobial susceptibility to 36 compounds, their virulence in the invertebrateGalleria mellonellamodel of infection, and their ability to form biofilm. Only the ΔacrBmutant displayed significantly different phenotypes compared to that of the wild-type strain: 4- to 32-fold decrease of MICs of several antibiotics, antiseptics, and dyes, increased production of biofilm, and attenuated virulence inG. mellonella. In order to identify specific substrates of each pump, we individually expressed intransall operons containing an RND pump-encoding gene into the ΔacrBhypersusceptible strain. We showed that three other RND-type efflux systems (ECL_00053-00055, ECL_01758-01759, and ECL_02124-02125) were able to partially restore the wild-type phenotype and to superadd to and even enlarge the broad range of antimicrobial resistance. This is the first global study assessing the role of all RND efflux pumps chromosomally encoded by the ECC, which confirms the major role of AcrB in both pathogenicity and resistance and the potential involvement of other RND-type members in acquired resistance.

scholarly journals Importance of Real-Time Assays To Distinguish Multidrug Efflux Pump-Inhibiting and Outer Membrane-Destabilizing Activities in Escherichia coli

2015 ◽  
Vol 197 (15) ◽  
pp. 2479-2488 ◽  
Author(s):  
Rajeev Misra ◽  
Keith D. Morrison ◽  
Hyun Jae Cho ◽  
Thanh Khuu
Keyword(s):  
Escherichia Coli ◽  
Membrane Permeability ◽  
Outer Membrane ◽  
Real Time ◽  
Efflux Pump ◽  
Membrane Integrity ◽  
Efflux Pumps ◽  
Permeability Barrier ◽  
Multidrug Efflux ◽  
Outer Membrane Permeability

ABSTRACTThe constitutively expressed AcrAB multidrug efflux system ofEscherichia colishows a high degree of homology with the normally silent AcrEF system. Exposure of a strain withacrABdeleted to antibiotic selection pressure frequently leads to the insertion sequence-mediated activation of the homologous AcrEF system. In this study, we used strains constitutively expressing either AcrAB or AcrEF from their normal chromosomal locations to resolve a controversy about whether phenylalanylarginine β-naphthylamide (PAβN) inhibits the activities of AcrAB and AcrEF and/or acts synergistically with antibiotics by destabilizing the outer membrane permeability barrier. Real-time efflux assays allowed a clear distinction between the efflux pump-inhibiting activity of PAβN and the outer membrane-destabilizing action of polymyxin B nonapeptide (PMXBN). When added in equal amounts, PAβN, but not PMXBN, strongly inhibited the efflux activities of both AcrAB and AcrEF pumps. In contrast, when outer membrane destabilization was assessed by the nitrocefin hydrolysis assay, PMXBN exerted a much greater damaging effect than PAβN. Strong action of PAβN in inhibiting efflux activity compared to its weak action in destabilizing the outer membrane permeability barrier suggests that PAβN acts mainly by inhibiting efflux pumps. We concluded that at low concentrations, PAβN acts specifically as an inhibitor of both AcrAB and AcrEF efflux pumps; however, at high concentrations, PAβN in the efflux-proficient background not only inhibits efflux pump activity but also destabilizes the membrane. The effects of PAβN on membrane integrity are compounded in cells unable to extrude PAβN.IMPORTANCEThe increase in multidrug-resistant bacterial pathogens at an alarming rate has accelerated the need for implementation of better antimicrobial stewardship, discovery of new antibiotics, and deeper understanding of the mechanism of drug resistance. The work carried out in this study highlights the importance of employing real-time fluorescence-based assays in differentiating multidrug efflux-inhibitory and outer membrane-destabilizing activities of antibacterial compounds.

scholarly journals Breaking the permeability barrier ofEscherichia coliby controlled hyperporination of the outer membrane.

2016 ◽  
pp. AAC.01882-16 ◽  
Author(s):  
Ganesh Krishnamoorthy ◽  
David Wolloscheck ◽  
Jon W. Weeks ◽  
Cameron Croft ◽  
Valentin V. Rybenkov ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Antibacterial Agents ◽  
Efflux Transporters ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Active Efflux ◽  
Efflux Inhibition ◽  
Membrane Barrier ◽  
Inhibitory Activities ◽  
Synergistic Relationship

In Gram-negative bacteria, a synergistic relationship between slow passive uptake of antibiotics across the outer membrane and active efflux transporters creates a permeability barrier, which efficiently reduces effective concentrations of antibiotics in cells and hence, their activities. To analyze the relative contributions of the active efflux and the passive barrier in activities of antibiotics, we constructedEscherichia colistrains with controllable permeability of the outer membrane. The strains express a large pore that does not discriminate compounds based on their hydrophilicity and sensitizes cells to a variety of antibacterial agents. We found that efficacies of antibiotics in these strains are specifically affected by either active efflux, slow uptake, or both, and reflect differences in the properties of the outer membrane barrier, repertoire of efflux pumps and inhibitory activities of antibiotics. Our results identify antibiotics which are the best candidates for potentiation of activities through efflux inhibition and permeabilization of the outer membrane.

scholarly journals Role of the Outer Membrane and Porins in Susceptibility of β-Lactamase-Producing Enterobacteriaceae to Ceftazidime-Avibactam

2015 ◽  
Vol 60 (3) ◽  
pp. 1349-1359 ◽  
Author(s):  
Jean-Marie Pagès ◽  
Sabine Peslier ◽  
Thomas A. Keating ◽  
Jean-Philippe Lavigne ◽  
Wright W. Nichols
Keyword(s):  
Membrane Permeability ◽  
Outer Membrane ◽  
Efflux Pump ◽  
Enterobacter Aerogenes ◽  
Antibacterial Activities ◽  
Clinical Isolates ◽  
Membrane Pore ◽  
Content Type ◽  
Porin Proteins ◽  
Outer Membrane Permeability

This study examined the activity of the novel antimicrobial combination ceftazidime-avibactam againstEnterobacteriaceaeexhibiting different outer membrane permeability profiles, specifically with or without porins and with or without expression of the main efflux pump (AcrAB-TolC). The addition of the outer membrane permeabilizer polymyxin B nonapeptide increased the antibacterial activities of avibactam alone, ceftazidime alone, and ceftazidime-avibactam against the characterized clinical isolates ofEscherichia coli,Enterobacter aerogenes, andKlebsiella pneumoniae. This enhancement of activities was mainly due to increased passive penetration of compounds since inhibition of efflux by the addition of phenylalanine-arginine β-naphthylamide affected the MICs minimally. OmpF (OmpK35) or OmpC (OmpK36) pores were not the major route by which avibactam crossed the outer membranes ofE. coliandK. pneumoniae. In contrast, Omp35 and Omp36 allowed diffusion of avibactam across the outer membrane ofE. aerogenes, although other diffusion channels for avibactam were also present in that species. It was clear that outer membrane permeability and outer membrane pore-forming proteins play a key role in the activity of ceftazidime-avibactam. Nevertheless, the MICs of ceftazidime-avibactam (with 4 mg/liter avibactam) against the ceftazidime-resistant clinical isolates of the three species ofEnterobacteriaceaestudied were ≤8 mg/liter, regardless of outer membrane permeability changes resulting from an absence of defined porin proteins or upregulation of efflux.

scholarly journals DpaA Detaches Braun’s Lipoprotein from Peptidoglycan

mBio ◽  
2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Matthias Winkle ◽  
Víctor M. Hernández-Rocamora ◽  
Karthik Pullela ◽  
Emily C. A. Goodall ◽  
Alessandra M. Martorana ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Cell Envelope ◽  
Stress Conditions ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Sequence Motifs ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Impermeable Barrier

ABSTRACT Gram-negative bacteria have a unique cell envelope with a lipopolysaccharide-containing outer membrane that is tightly connected to a thin layer of peptidoglycan. The tight connection between the outer membrane and peptidoglycan is needed to maintain the outer membrane as an impermeable barrier for many toxic molecules and antibiotics. Enterobacteriaceae such as Escherichia coli covalently attach the abundant outer membrane-anchored lipoprotein Lpp (Braun’s lipoprotein) to tripeptides in peptidoglycan, mediated by the transpeptidases LdtA, LdtB, and LdtC. LdtD and LdtE are members of the same family of ld-transpeptidases but they catalyze a different reaction, the formation of 3-3 cross-links in the peptidoglycan. The function of the sixth homologue in E. coli, LdtF, remains unclear, although it has been shown to become essential in cells with inhibited lipopolysaccharide export to the outer membrane. We now show that LdtF hydrolyzes the Lpp-peptidoglycan linkage, detaching Lpp from peptidoglycan, and have renamed LdtF to peptidoglycan meso-diaminopimelic acid protein amidase A (DpaA). We show that the detachment of Lpp from peptidoglycan is beneficial for the cell under certain stress conditions and that the deletion of dpaA allows frequent transposon inactivation in the lapB (yciM) gene, whose product downregulates lipopolysaccharide biosynthesis. DpaA-like proteins have characteristic sequence motifs and are present in many Gram-negative bacteria, of which some have no Lpp, raising the possibility that DpaA has other substrates in these species. Overall, our data show that the Lpp-peptidoglycan linkage in E. coli is more dynamic than previously appreciated. IMPORTANCE Gram-negative bacteria have a complex cell envelope with two membranes and a periplasm containing the peptidoglycan layer. The outer membrane is firmly connected to the peptidoglycan by highly abundant proteins. The outer membrane-anchored Braun’s lipoprotein (Lpp) is the most abundant protein in E. coli, and about one-third of the Lpp molecules become covalently attached to tripeptides in peptidoglycan. The attachment of Lpp to peptidoglycan stabilizes the cell envelope and is crucial for the outer membrane to function as a permeability barrier for a range of toxic molecules and antibiotics. So far, the attachment of Lpp to peptidoglycan has been considered to be irreversible. We have now identified an amidase, DpaA, which is capable of detaching Lpp from peptidoglycan, and we show that the detachment of Lpp is important under certain stress conditions. DpaA-like proteins are present in many Gram-negative bacteria and may have different substrates in these species.

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