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Rapid conversion of Pseudomonas aeruginosa to a spherical cell morphotype facilitates tolerance to carbapenems and penicillins but increases susceptibility to antimicrobial peptides.

ABSTRACT: The Gram-negative human pathogen Pseudomonas aeruginosa tolerates high concentrations of ?-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying ?-lactam tolerance are currently unclear. Here, we show that P. aeruginosa undergoes a rapid en masse transition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with ?-lactams from the widely used carbapenem and penicillin classes. When the antibiotic is removed, the entire population of spherical cells quickly converts back to the normal bacillary form. Our results demonstrate that these rapid population-wide cell morphotype transitions function as a strategy to survive antibiotic exposure. Taking advantage of these findings, we have developed a novel approach to efficiently kill P. aeruginosa by using carbapenem treatment to induce en masse transition to the spherical cell morphotype and then exploiting the relative fragility and sensitivity of these cells to killing by antimicrobial peptides (AMPs) that are relatively inactive against P. aeruginosa bacillary cells. This approach could broaden the repertoire of antimicrobial compounds used to treat P. aeruginosa and serve as a basis for developing new therapeutic agents to combat bacterial infections.

SUBMITTER: Monahan LG

PROVIDER: S-EPMC4023726 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Rapid conversion of Pseudomonas aeruginosa to a spherical cell morphotype facilitates tolerance to carbapenems and penicillins but increases susceptibility to antimicrobial peptides.

Monahan Leigh G LG Turnbull Lynne L Osvath Sarah R SR Birch Debra D Charles Ian G IG Whitchurch Cynthia B CB

Antimicrobial agents and chemotherapy 20140113 4

The Gram-negative human pathogen Pseudomonas aeruginosa tolerates high concentrations of β-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying β-lactam tolerance are currently unclear. Here, we show that P. aeruginosa undergoes a rapid en masse transition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with β-lactams from the w ...[more]

PMID: 24419348

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Project description:BACKGROUND: The respiratory tract epithelium is a critical environmental interface that regulates inflammation. In chronic infectious airway diseases, pathogens may permanently colonize normally sterile luminal environments. Host-pathogen interactions determine the intensity of inflammation and thus, rates of tissue injury. Although many cells become refractory to stimulation by pathogen products, it is unknown whether the airway epithelium becomes either tolerant or hypersensitive in the setting of chronic infection. Our goals were to characterize the response of well-differentiated primary human tracheobronchial epithelial cells to Pseudomonas aeruginosa, to understand whether repeated exposure induced tolerance and, if so, to explore the mechanism(s). METHODS: The apical surface of well-differentiated primary human tracheobronchial epithelial cell cultures was repetitively challenged with Pseudomonas aeruginosa culture filtrates or the bacterial media control. Toxicity, cytokine production, signal transduction events and specific effects of dominant negative forms of signaling molecules were examined. Additional experiments included using IL-1beta and TNFalpha as challenge agents, and performing comparative studies with a novel airway epithelial cell line. RESULTS: An initial challenge of the apical surface of polarized human airway epithelial cells with Pseudomonas aeruginosa culture filtrates induced phosphorylation of IRAK1, JNK, p38, and ERK, caused degradation of IkappaBalpha, generation of NF-kappaB and AP-1 transcription factor activity, and resulted in IL-8 secretion, consistent with activation of the Toll-like receptor signal transduction pathway. These responses were strongly attenuated following a second Pseudomonas aeruginosa, or IL-1beta, but not TNFalpha, challenge. Tolerance was associated with decreased IRAK1 protein content and kinase activity and dominant negative IRAK1 inhibited Pseudomonas aeruginosa--stimulated NF-kappaB transcriptional activity. CONCLUSION: The airway epithelial cell response to Pseudomonas aeruginosa entails adaptation and tolerance likely mediated, in part, by down-regulation of IRAK1.

Project description:Competitive interactions mediated by released chemicals (e.g., toxins) are prominent in multispecies communities, but the effects of these chemicals at subinhibitory concentrations on susceptible bacteria are poorly understood. Although Pseudomonas aeruginosa and species of the Burkholderia cepacia complex (Bcc) can exist together as a coinfection in cystic fibrosis airways, P. aeruginosa toxins can kill Bcc species in vitro Consequently, these bacteria become an ideal in vitro model system to study the impact of sublethal levels of toxins on the biology of typical susceptible bacteria, such as the Bcc, when exposed to P. aeruginosa toxins. Using P. aeruginosa spent medium as a source of toxins, we showed that a small window of subinhibitory concentrations modulated the colony morphotype and swarming motility of some but not all tested Bcc strains, for which rhamnolipids were identified as the active molecule. Using a random transposon mutagenesis approach, we identified several genes required by the Bcc to respond to low concentrations of rhamnolipids and consequently affect the ability of this microbe to change its morphotype and swarm over surfaces. Among those genes identified were those coding for type IVb-Tad pili, which are often required for virulence in various bacterial pathogens. Our study demonstrates that manipulating chemical gradients in vitro can lead to the identification of bacterial behaviors relevant to polymicrobial infections.IMPORTANCE Interspecies interactions can have profound effects on the development and outcomes of polymicrobial infections. Consequently, improving the molecular understanding of these interactions could provide us with new insights on the possible long-term consequences of these chronic infections. In this study, we show that P. aeruginosa-derived rhamnolipids, which participate in Bcc killing at high concentrations, can also trigger biological responses in Burkholderia spp. at low concentrations. The modulation of potential virulence phenotypes in the Bcc by P. aeruginosa suggests that these interactions contribute to pathogenesis and disease severity in the context of polymicrobial infections.

Dataset Information

Rapid conversion of Pseudomonas aeruginosa to a spherical cell morphotype facilitates tolerance to carbapenems and penicillins but increases susceptibility to antimicrobial peptides.

Publications

Rapid conversion of Pseudomonas aeruginosa to a spherical cell morphotype facilitates tolerance to carbapenems and penicillins but increases susceptibility to antimicrobial peptides.

Similar Datasets

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