Klebsiella pneumoniae Reduces SUMOylation To Limit Host Defense Responses

ABSTRACT Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here, we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells, Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48 ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCF-βTrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-extracellular signal-regulated kinase (ERK)-glycogen synthase kinase 3 beta (GSK3β) signaling pathway-dependent manner. In macrophages, Toll-like receptor 4 (TLR4)-TRAM-TRIF-induced type I interferon (IFN) via IFN receptor 1 (IFNAR1)-controlled signaling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 microRNAs (miRNAs). Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule, and the lipopolysaccharide (LPS) O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. A Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages. IMPORTANCE Klebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last-line” antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug-resistant Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular levels in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defenses by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.

Download Full-text

Klebsiella pneumoniae reduces SUMOylation to limit host defence responses

10.1101/2020.06.29.179275 ◽

2020 ◽

Author(s):

Joana Sá-Pessoa ◽

Kornelia Przybyszewska ◽

Filipe Nuno Vasconcelos ◽

Amy Dumigan ◽

Christian G. Frank ◽

...

Keyword(s):

Epithelial Cells ◽

Klebsiella Pneumoniae ◽

Inflammatory Responses ◽

Treatment Options ◽

Multidrug Resistant ◽

Cellular Level ◽

Lung Epithelial Cells ◽

Type I ◽

Dependent Manner ◽

Medical Needs

ABSTRACTKlebsiella pneumoniae is an important cause of multidrug resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48-ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCFβ-TrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an EGFR-PI3K-AKT-ERK-GSK3β signalling pathway dependent manner. In macrophages, TLR4-TRAM-TRIF induced type-I IFN via IFNAR1-controlled signalling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 miRNAs. Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule and the LPS O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages.IMPORTANCEKlebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last line” antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular level in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defences by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.

Download Full-text

Epigenomics, genomics, resistome, mobilome, virulome and evolutionary phylogenomics of carbapenem-resistant Klebsiella pneumoniae clinical strains

Microbial Genomics ◽

10.1099/mgen.0.000474 ◽

2020 ◽

Vol 6 (12) ◽

Author(s):

Katlego Kopotsa ◽

Nontombi M. Mbelle ◽

John Osei Sekyere

Keyword(s):

Klebsiella Pneumoniae ◽

Multidrug Resistant ◽

Type I ◽

Bacteriophage Therapy ◽

Content Type ◽

Carbapenem Resistant ◽

Plasmid Replicon ◽

Size Number ◽

Plasmid Size ◽

Epidemiological Trends

Carbapenem-resistant Klebsiella pneumoniae (CRKP) remains a major clinical pathogen and public health threat with few therapeutic options. The mobilome, resistome, methylome, virulome and phylogeography of CRKP in South Africa and globally were characterized. CRKP collected in 2018 were subjected to antimicrobial susceptibility testing, screening by multiplex PCR, genotyping by repetitive element palindromic (REP)-PCR, plasmid size, number, incompatibility and mobility analyses, and PacBio’s SMRT sequencing (n=6). There were 56 multidrug-resistant CRKP, having bla OXA-48-like and bla NDM-1/7 carbapenemases on self-transmissible IncF, A/C, IncL/M and IncX3 plasmids endowed with prophages, traT, resistance islands, and type I and II restriction modification systems (RMS). Plasmids and clades detected in this study were respectively related to globally established/disseminated plasmids clades/clones, evincing transboundary horizontal and vertical dissemination. Reduced susceptibility to colistin occurred in 23 strains. Common clones included ST307, ST607, ST17, ST39 and ST3559. IncFIIk virulent plasmid replicon was present in 56 strains. Whole-genome sequencing of six strains revealed least 41 virulence genes, extensive ompK36 mutations, and four different K- and O-loci types: KL2, KL25, KL27, KL102, O1, O2, O4 and O5. Types I, II and III RMS, conferring m6A (G A TC, G A TGNNNNNNTTG, CA A NNNNNNCATC motifs) and m4C (C C WGG) modifications on chromosomes and plasmids, were found. The nature of plasmid-mediated, clonal and multi-clonal dissemination of blaOXA-48-like and blaNDM-1 mirrors epidemiological trends observed for closely related plasmids and sequence types internationally. Worryingly, the presence of both bla OXA-48 and bla NDM-1 in the same isolates was observed. Plasmid-mediated transmission of RMS, virulome and prophages influence bacterial evolution, epidemiology, pathogenicity and resistance, threatening infection treatment. The influence of RMS on antimicrobial and bacteriophage therapy needs urgent investigation.

Download Full-text

Emergence and Evolution of Multidrug-Resistant Klebsiella pneumoniae with both blaKPC and blaCTX-M Integrated in the Chromosome

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00076-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 30

Author(s):

Weihua Huang ◽

Guiqing Wang ◽

Robert Sebra ◽

Jian Zhuge ◽

Changhong Yin ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Klebsiella Pneumoniae ◽

Resistance Genes ◽

De Novo ◽

Genomic Analysis ◽

Multidrug Resistant ◽

Comparative Genomic ◽

Type I ◽

Content Type ◽

Antimicrobial Resistance Genes

ABSTRACT The extended-spectrum-β-lactamase (ESBL)- and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae represent serious and urgent threats to public health. In a retrospective study of multidrug-resistant K. pneumoniae, we identified three clinical isolates, CN1, CR14, and NY9, carrying both bla CTX-M and bla KPC genes. The complete genomes of these three K. pneumoniae isolates were de novo assembled by using both short- and long-read whole-genome sequencing. In CR14 and NY9, bla CTX-M and bla KPC were carried on two different plasmids. In contrast, CN1 had one copy of bla KPC-2 and three copies of bla CTX-M-15 integrated in the chromosome, for which the bla CTX-M-15 genes were linked to an insertion sequence, ISEcp1, whereas the bla KPC-2 gene was in the context of a Tn4401a transposition unit conjugated with a PsP3-like prophage. Intriguingly, downstream of the Tn4401a-bla KPC-2-prophage genomic island, CN1 also carried a clustered regularly interspaced short palindromic repeat (CRISPR)-cas array with four spacers targeting a variety of K. pneumoniae plasmids harboring antimicrobial resistance genes. Comparative genomic analysis revealed that there were two subtypes of type I-E CRISPR-cas in K. pneumoniae strains and suggested that the evolving CRISPR-cas, with its acquired novel spacer, induced the mobilization of antimicrobial resistance genes from plasmids into the chromosome. The integration and dissemination of multiple copies of bla CTX-M and bla KPC from plasmids to chromosome depicts the complex pandemic scenario of multidrug-resistant K. pneumoniae. Additionally, the implications from this study also raise concerns for the application of a CRISPR-cas strategy against antimicrobial resistance.

Download Full-text

Klebsiella pneumoniae Translocates across the Intestinal Epithelium via Rho GTPase- and Phosphatidylinositol 3-Kinase/Akt-Dependent Cell Invasion

Infection and Immunity ◽

10.1128/iai.02345-14 ◽

2014 ◽

Vol 83 (2) ◽

pp. 769-779 ◽

Cited By ~ 27

Author(s):

Chun-Ru Hsu ◽

Yi-Jiun Pan ◽

Ju-Yun Liu ◽

Chun-Tang Chen ◽

Tzu-Lung Lin ◽

...

Keyword(s):

Epithelial Cells ◽

Klebsiella Pneumoniae ◽

Cell Invasion ◽

Intestinal Epithelium ◽

Intestinal Barrier ◽

Dependent Manner ◽

Phosphatidylinositol 3 Kinase ◽

Content Type ◽

Junction Protein ◽

Phosphatidylinositol 3

Klebsiella pneumoniaeis an important pathogen that causes hospital-acquired septicemia and is associated with the recent emergence of community-acquired pyogenic liver abscess (PLA). Clinical typing suggests thatK. pneumoniaeinfections originate from the gastrointestinal reservoir. However, the underlying mechanism remains unknown. Here, we have sought to determine howK. pneumoniaepenetrates the intestinal barrier. We identified that bacteremia and PLA clinical isolates adhered to and invaded intestinal epithelial cells. Internalization ofK. pneumoniaein three different human colonic cell lines was visualized by confocal microscopy and three-dimensional (3D) imaging. Using a Transwell system, we demonstrated that theseK. pneumoniaeisolates translocated across a polarized Caco-2 monolayer. No disruptions of transepithelial electrical resistance and altered distribution of tight junction protein ZO-1 or occludin were observed. Therefore,K. pneumoniaeappeared to penetrate the intestinal epithelium via a transcellular pathway. Using specific inhibitors, we characterized the host signaling pathways involved. Inhibition by cytochalasin D and nocodazole suggested that actin and microtubule cytoskeleton were both important forK. pneumoniaeinvasion. A Rho inhibitor, ML141, LY294002, and an Akt1/2 inhibitor diminishedK. pneumoniaeinvasion in a dose-dependent manner, indicating that Rho family GTPases and phosphatidylinositol 3-kinase (PI3K)/Akt signaling were required. By a mouse model of gastrointestinal colonization,in vivoinvasion ofK. pneumoniaeinto colonic epithelial cells was demonstrated. Our results present evidence to describe a possible mechanism of gastrointestinal translocation forK. pneumoniae. Cell invasion by manipulating host machinery provides a pathway for gut-colonizedK. pneumoniaecells to penetrate the intestinal barrier and access extraintestinal locations to cause disease.

Download Full-text

EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells

Cancers ◽

10.3390/cancers13051079 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1079

Author(s):

Manuela Zangrossi ◽

Patrizia Romani ◽

Probir Chakravarty ◽

Colin D.H. Ratcliffe ◽

Steven Hooper ◽

...

Keyword(s):

Breast Cancer ◽

Epithelial Cells ◽

Cancer Cells ◽

Lung Epithelial Cells ◽

Late Relapse ◽

Alveolar Type ◽

Type I ◽

Extrinsic Factors ◽

Lung Epithelial

Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs.

Download Full-text

Lung Epithelial Regulation of BCL2 Related Protein A1 (BCL2A1) by Coronaviruses (SARS-CoV) and Type I Interferon Signaling

10.1101/2021.07.21.453244 ◽

2021 ◽

Author(s):

Ramana Chilakamarti

Keyword(s):

Epithelial Cells ◽

Human Lung ◽

Type I Interferon ◽

Respiratory Viruses ◽

Lung Epithelial Cells ◽

Type I ◽

Related Protein ◽

Interferon Signaling ◽

Lung Epithelial ◽

Human Lung Epithelial Cells

Highly pathogenic respiratory viruses such as 1918 influenza (HIN1) and coronavirus (SARS-CoV-2) induce significant lung injury with diffuse alveolar damage, capillary leak, and extensive cell death resulting in acute respiratory distress syndrome (ARDS). Direct effects of the virus, as well as host immune response such as proinflammatory cytokine production, contribute to programmed cell death or apoptosis. Alveolar lung epithelial type II (AT2) cells play a major role in the clearance of respiratory viruses, secretion of surfactant proteins and antimicrobial substances into the bronchoalveolar fluid as well as repair of lung injury. Gene expression in AT2 cells is regulated in a tissue and cell-specific manner and in a temporal fashion. The availability of tissue and cell-specific RNA datasets in Human Protein Atlas led to the identification of localized expression patterns of BCL-2 family members such as BCL2 related protein A1 (BCL2A1) in AT2 cells and immune cells of the lung. BCL2A1 expression was regulated by multiple stimuli including Toll-like receptor (TLR) ligands, interferons (IFNs), inflammatory cytokines, and inhibited by the steroid dexamethasone. In this study, regulation of BCL2A1 gene expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. SARS-CoV-2 infection significantly induced BCL2A1 expression in human lung epithelial cells within 24 hours that required the expression of Angiotensin-converting enzyme 2 (ACE2). BCL2A1 mRNA induction by SARS-CoV-2 was correlated with the induced expression of IFN-β and IFN-regulated transcription factor mRNA. BCL2A1 was induced by IFN-β treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE cells. Furthermore, bioinformatics revealed that a subset of BCL-2 family members involved in the control of apoptosis and transcription such as BCL2A1, BCL2L14, BCL3, and BCL6 were regulated in the lung epithelial cells by coronaviruses and in the lung tissue samples of COVID-19 patients. Transcriptomic data also suggested that these genes were differentially regulated by the steroid drug dexamethasone.

Download Full-text

Transcriptional Response of Multidrug-Resistant Klebsiella pneumoniae Clinical Isolates to Ciprofloxacin Stress

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2021/5570963 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Roman Farooq Alvi ◽

Bilal Aslam ◽

Muhammad Hidayat Rasool ◽

Saima Muzammil ◽

Abu Baker Siddique ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Stress Responses ◽

Genetic Resistance ◽

Transcriptional Response ◽

Multidrug Resistant ◽

Mrna Levels ◽

Dependent Manner ◽

Isolation And Identification ◽

Concentration Dependent Manner ◽

High Level

Background. The term “persisters” refers to a small bacterial population that persists during treatment with high antibiotic concentration or dose in the absence of genetic resistance. The present study was designed to investigate the transcriptional response in indigenous Klebsiella pneumoniae under the ciprofloxacin stress. Methods. Isolation and identification of K. pneumoniae were carried out through standard microbiological protocols. The characterization of quinolone resistance was performed by estimating the quinolone susceptibility testing, MIC estimation, and detecting the QRDR and PMQR. Transcriptional response of the isolates to ciprofloxacin was determined using qPCR. Results. Among 34 isolates, 23 (67%) were resistant to ciprofloxacin. Both QRDR (gyrA and gyrB) and PMQR (qnrA, qnrB, and qnrS) were detected in the isolates, and all were found resistant to ciprofloxacin. The mRNA levels of both mutS and euTu under the influence of ciprofloxacin were significantly increased. On ciprofloxacin exposure, the mRNA levels of the DNA damage response element (mutS) were raised in a time-dependent fashion. K. pneumoniae showed high-level resistance to ciprofloxacin in the presence of mutations in QRDR and PMQR genes. Conclusion. The transcriptional response revealed the upregulation of DNA repair and protein folding elements (mutS and euTu) in ciprofloxacin stress and delayed cell division. The ciprofloxacin was found to trigger various stress responses in a time- and concentration-dependent manner.

Download Full-text

Genomic evolution and local epidemiology of Klebsiella pneumoniae from a major hospital in Beijing, China, over a 15 year period: dissemination of known and novel high-risk clones

Microbial Genomics ◽

10.1099/mgen.0.000520 ◽

2021 ◽

Author(s):

Mattia Palmieri ◽

Kelly L. Wyres ◽

Caroline Mirande ◽

Zhao Qiang ◽

Ye Liyan ◽

...

Keyword(s):

High Risk ◽

Klebsiella Pneumoniae ◽

Type Species ◽

Treatment Options ◽

Multidrug Resistant ◽

Virulence Plasmid ◽

Content Type ◽

Origin And Evolution ◽

Link Type ◽

Beijing China

Klebsiella pneumoniae is a frequent cause of nosocomial and severe community-acquired infections. Multidrug-resistant (MDR) and hypervirulent (hv) strains represent major threats, and tracking their emergence, evolution and the emerging convergence of MDR and hv traits is of major importance. We employed whole-genome sequencing (WGS) to study the evolution and epidemiology of a large longitudinal collection of clinical K. pneumoniae isolates from the H301 hospital in Beijing, China. Overall, the population was highly diverse, although some clones were predominant. Strains belonging to clonal group (CG) 258 were dominant, and represented the majority of carbapenemase-producers. While CG258 strains showed high diversity, one clone, ST11-KL47, represented the majority of isolates, and was highly associated with the KPC-2 carbapenemase and several virulence factors, including a virulence plasmid. The second dominant clone was CG23, which is the major hv clone globally. While it is usually susceptible to multiple antibiotics, we found some isolates harbouring MDR plasmids encoding for ESBLs and carbapenemases. We also reported the local emergence of a recently described high-risk clone, ST383. Conversely to strains belonging to CG258, which are usually associated to KPC-2, ST383 strains seem to readily acquire carbapenemases of different types. Moreover, we found several ST383 strains carrying the hypervirulence plasmid. Overall, we detected about 5 % of simultaneous carriage of AMR genes (ESBLs or carbapenemases) and hypervirulence genes. Tracking the emergence and evolution of such strains, causing severe infections with limited treatment options, is fundamental in order to understand their origin and evolution and to limit their spread. This article contains data hosted by Microreact.

Download Full-text

Complete Genome Sequence of Klebsiella pneumoniae Phage Sweeny

Microbiology Resource Announcements ◽

10.1128/mra.01047-19 ◽

2019 ◽

Vol 8 (39) ◽

Cited By ~ 1

Author(s):

Nicholas Martinez ◽

Eric Williams ◽

Heather Newkirk ◽

Mei Liu ◽

Jason J. Gill ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Complete Genome Sequence ◽

Protein Level ◽

Multidrug Resistant ◽

Content Type ◽

Hospital Acquired Infections ◽

Multidrug Resistant Bacterium ◽

Protein Encoding ◽

Hospital Acquired ◽

Encoding Genes

Klebsiella pneumoniae is a multidrug-resistant bacterium causing many severe hospital-acquired infections. Here, we describe siphophage Sweeny that infects K. pneumoniae. Of its 78 predicted protein-encoding genes, a functional assignment was given to 36 of them. Sweeny is most closely related to T1-like phages at the protein level.

Download Full-text

Complex Response of the CpxAR Two-Component System to β-Lactams on Antibiotic Resistance and Envelope Homeostasis in Enterobacteriaceae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00291-20 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 1

Author(s):

Muriel Masi ◽

Elizabeth Pinet ◽

Jean-Marie Pagès

Keyword(s):

Efflux Pump ◽

Multidrug Resistant ◽

Diaminopimelic Acid ◽

Single Amino Acid ◽

Dependent Manner ◽

Content Type ◽

Promising Therapeutic Target ◽

Abnormal Accumulation ◽

A Cell ◽

Mutational Activation

ABSTRACT The Cpx stress response is widespread among Enterobacteriaceae. We previously reported a mutation in cpxA in a multidrug-resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields a single-amino-acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxAY144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the effect of the intimate interconnection between the Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall-active antibiotic or by inactivating penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increases phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to cause abnormal accumulation of muropeptides (disaccharide-pentapeptide and N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycans caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular, the interaction between CpxA and CpxP, as a promising therapeutic target.

Download Full-text