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A multifaceted cellular damage repair and prevention pathway promotes high-level tolerance to β-lactam antibiotics.

ABSTRACT: Bactericidal antibiotics are powerful agents due to their ability to convert essential bacterial functions into lethal processes. However, many important bacterial pathogens are remarkably tolerant against bactericidal antibiotics due to inducible damage repair responses. The cell wall damage response two-component system VxrAB of the gastrointestinal pathogen Vibrio cholerae promotes high-level β-lactam tolerance and controls a gene network encoding highly diverse functions, including negative control over multiple iron uptake systems. How this system contributes to tolerance is poorly understood. Here, we show that β-lactam antibiotics cause an increase in intracellular free iron levels and collateral oxidative damage, which is exacerbated in the ∆vxrAB mutant. Mutating major iron uptake systems dramatically increases ∆vxrAB tolerance to β-lactams. We propose that VxrAB reduces antibiotic-induced toxic iron and concomitant metabolic perturbations by downregulating iron uptake transporters and show that iron sequestration enhances tolerance against β-lactam therapy in a mouse model of cholera infection. Our results suggest that a microorganism's ability to counteract diverse antibiotic-induced stresses promotes high-level antibiotic tolerance and highlights the complex secondary responses elicited by antibiotics.

SUBMITTER: Shin JH

PROVIDER: S-EPMC7857431 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A multifaceted cellular damage repair and prevention pathway promotes high level tolerance to b-lactam antibiotics

Project description:Bactericidal antibiotics are powerful agents due to their ability to convert essential bacterial functions into lethal processes. However, many important bacterial pathogens are remarkably tolerant against bactericidal antibiotics due to inducible damage repair responses. The cell wall damage response two-component system VxrAB of the gastrointestinal pathogen Vibrio cholerae promotes high-level b-lactam tolerance and controls a gene network encoding highly diverse functions, including negative control over multiple iron uptake systems. How this system contributes to tolerance is poorly understood. Here, we show that b-lactam antibiotics cause an increase in intracellular free iron levels and collateral oxidative damage, which is exacerbated in the ?vxrAB mutant. Mutating major iron uptake systems drastically increases ?vxrAB tolerance to b-lactams. We propose that VxrAB reduces antibiotic-induced toxic iron and concomitant metabolic perturbations by downregulating iron uptake transporters and show that iron sequestration enhances tolerance against b-lactam therapy in a mouse model of cholera infection. Our results suggest that a microorganism's ability to counteract diverse antibiotic-induced stresses promotes high-level antibiotic tolerance, and highlights the complex secondary responses elicited by antibiotics.

| S-SCDT-EMBOR-2020-51790-T | biostudies-other

Mechanisms of damage prevention, signalling and repair impact disease tolerance.

Project description:The insect gut is frequently exposed to pathogenic threats and must not only clear these potential infections, but also tolerate relatively high microbe loads. In contrast to the mechanisms that eliminate pathogens, we currently know less about the mechanisms of disease tolerance. We investigated how well-described mechanisms that prevent, signal, control or repair damage during infection contribute to the phenotype of disease tolerance. We established enteric infections with the bacterial pathogen Pseudomonas entomophila in transgenic lines of Drosophila melanogaster fruit flies affecting dcy (a major component of the peritrophic matrix), upd3 (a cytokine-like molecule), irc (a negative regulator of reactive oxygen species) and egfr1 (epithelial growth factor receptor). Flies lacking dcy experienced the highest mortality, while loss of function of either irc or upd3 reduced tolerance in both sexes. The disruption of egfr1 resulted in a severe loss in tolerance in male flies but had no substantial effect on the ability of female flies to tolerate P. entomophila infection, despite carrying greater microbe loads than males. Together, our findings provide evidence for the role of damage limitation mechanisms in disease tolerance and highlight how sexual dimorphism in these mechanisms could generate sex differences in infection outcomes.

| S-EPMC9382215 | biostudies-literature

Endopeptidase-mediated beta lactam tolerance.

Project description:In many bacteria, inhibition of cell wall synthesis leads to cell death and lysis. The pathways and enzymes that mediate cell lysis after exposure to cell wall-acting antibiotics (e.g. beta lactams) are incompletely understood, but the activities of enzymes that degrade the cell wall ('autolysins') are thought to be critical. Here, we report that Vibrio cholerae, the cholera pathogen, is tolerant to antibiotics targeting cell wall synthesis. In response to a wide variety of cell wall--acting antibiotics, this pathogen loses its rod shape, indicative of cell wall degradation, and becomes spherical. Genetic analyses revealed that paradoxically, V. cholerae survival via sphere formation required the activity of D,D endopeptidases, enzymes that cleave the cell wall. Other autolysins proved dispensable for this process. Our findings suggest the enzymes that mediate cell wall degradation are critical for determining bacterial cell fate--sphere formation vs. lysis--after treatment with antibiotics that target cell wall synthesis.

| S-EPMC4401780 | biostudies-literature

Could β-Lactam Antibiotics Block Humoral Immunity?

Project description:It has been reported that treatment with β-lactam antibiotics induces leukopenia and candidemia, worsens the clinical response to anticancer immunotherapy and decreases immune response to vaccination. β-lactamases can cleave β-lactam antibiotics by blocking their activity. Two distincts superfamilies of β-lactamases are described, the serine β-lactamases and the zinc ion dependent metallo-β-lactamases. In human, 18 metallo-β-lactamases encoding genes (hMBLs) have been identified. While the physiological role of most of them remains unknown, it is well established that the SNM1A, B and C proteins are involved in DNA repair. The SNM1C/Artemis protein is precisely associated in the V(D)J segments rearrangement, that leads to immunoglobulin (Ig) and T-cell receptor variable regions, which have a crucial role in the immune response. Thus in humans, SNM1C/Artemis mutation is associated with severe combined immunodeficiency characterized by hypogammaglobulinemia deficient cellular immunity and opportunistic infections. While catalytic site of hMBLs and especially that of the SNM1 family is highly conserved, in vitro studies showed that some β-lactam antibiotics, and precisely third generation of cephalosporin and ampicillin, inhibit the metallo-β-lactamase proteins SNM1A & B and the SNM1C/Artemis protein complex. By analogy, the question arises as to whether β-lactam antibiotics can block the SNM1C/Artemis protein in humans inducing transient immunodeficiency. We reviewed here the literature data supporting this hypothesis based on in silico, in vitro and in vivo evidences. Understanding the impact of β-lactam antibiotics on the immune cell will offer new therapeutic clues and new clinical approaches in oncology, immunology, and infectious diseases.

| S-EPMC8480522 | biostudies-literature

Oligoribonuclease Contributes to Tolerance to Aminoglycoside and β-Lactam Antibiotics by Regulating KatA in Pseudomonas aeruginosa.

Project description:Pseudomonas aeruginosa is an opportunistic bacterial pathogen and is intrinsically resistant to a variety of antibiotics. Oligoribonuclease (Orn) is a 3'-to-5' exonuclease that degrades nanoRNAs. The Orn controls biofilm formation by influencing the homeostasis of cyclic-di-GMP. Previously, we demonstrated that Orn contributes to the tolerance of P. aeruginosa to fluoroquinolone antibiotics by affecting the production of pyocins. In this study, we found that mutation in the orn gene reduces bacterial tolerance to aminoglycoside and β-lactam antibiotics, which is mainly due to a defective response to oxidative stresses. The major catalase KatA is downregulated in the orn mutant, and overexpression of the katA gene restores the bacterial tolerance to oxidative stresses and the antibiotics. We further demonstrated that Orn influenced the translation of the katA mRNA and narrowed down the region in the katA mRNA that is involved in the regulation of its translation. Therefore, our results revealed a novel role of the Orn in bacterial tolerance to oxidative stresses as well as aminoglycoside and β-lactam antibiotics.

| S-EPMC6535506 | biostudies-literature

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin.

Project description:Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell-mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

| S-EPMC3581969 | biostudies-literature

Cephalosporins as key lead generation beta-lactam antibiotics.

Project description:Antibiotics are antibacterial compounds that interfere with bacterial growth, without harming the infected eukaryotic host. Among the clinical agents, beta-lactams play a major role in treating infected humans and animals. However, the ever-increasing antibiotic resistance crisis is forcing the pharmaceutical industry to search for new antibacterial drugs to combat a range of current and potential multi-resistant bacterial pathogens. In this review, we provide an overview of the development, innovation, and current status of therapeutic applications for beta-lactams with a focus on semi-synthetic cephalosporins. Cephalosporin C (CPC), which is a natural secondary metabolite from the filamentous fungus Acremonium chrysogenum, plays a major and demanding role in both producing modern antibiotics and developing new ones. CPC serves as a core compound for producing semi-synthetic cephalosporins that can control infections with different resistance mechanisms. We therefore summarize our latest knowledge about the CPC biosynthetic pathway and its regulation in the fungal host. Finally, we describe how CPC serves as a key lead generation source for the in vitro and better, in vivo synthesis of 7-aminocephalosporanic acid (7-ACA), the major core compound for the pharmaceutical synthesis of current and future semi-synthetic cephalosporins. KEY POINTS: • Latest literature on cephalosporin generations • Biotechnical production of cephalosporins • In vivo production of 7-ACA.

| S-EPMC9712332 | biostudies-literature

Distinct single-cell morphological dynamics under beta-lactam antibiotics.

Project description:The bacterial cell wall is conserved in prokaryotes, stabilizing cells against osmotic stress. Beta-lactams inhibit cell-wall synthesis and induce lysis through a bulge-mediated mechanism; however, little is known about the formation dynamics and stability of these bulges. To capture processes of different timescales, we developed an imaging platform combining automated image analysis with live-cell microscopy at high time resolution. Beta-lactam killing of Escherichia coli cells proceeded through four stages: elongation, bulge formation, bulge stagnation, and lysis. Both the cell wall and outer membrane (OM) affect the observed dynamics; damaging the cell wall with different beta-lactams and compromising OM integrity cause different modes and rates of lysis. Our results show that the bulge-formation dynamics are determined by how the cell wall is perturbed. The OM plays an independent role in stabilizing the bulge once it is formed. The stabilized bulge delays lysis and allows recovery upon drug removal.

| S-EPMC3525771 | biostudies-literature

Novel metagenome-derived carboxylesterase that hydrolyzes β-lactam antibiotics.

Project description:It has been proposed that family VIII carboxylesterases and class C β-lactamases are phylogenetically related; however, none of carboxylesterases has been reported to hydrolyze β-lactam antibiotics except nitrocefin, a nonclinical chromogenic substrate. Here, we describe the first example of a novel carboxylesterase derived from a metagenome that is able to cleave the amide bond of various β-lactam substrates and the ester bond of p-nitrophenyl esters. A clone with lipolytic activity was selected by functional screening of a metagenomic library using tributyrin agar plates. The sequence analysis of the clone revealed the presence of an open reading frame (estU1) encoding a polypeptide of 426 amino acids, retaining an S-X-X-K motif that is conserved in class C β-lactamases and family VIII carboxylesterases. The gene was overexpressed in Escherichia coli, and the purified recombinant protein (EstU1) was further characterized. EstU1 showed esterase activity toward various chromogenic p-nitrophenyl esters. In addition, it exhibited hydrolytic activity toward nitrocefin, leading us to investigate whether EstU1 could hydrolyze β-lactam antibiotics. EstU1 was able to hydrolyze first-generation β-lactam antibiotics, such as cephalosporins, cephaloridine, cephalothin, and cefazolin. In a kinetic study, EstU1 showed a similar range of substrate affinities for both p-nitrophenyl butyrate and first-generation cephalosporins while the turnover efficiency for the latter was much lower. Furthermore, site-directed mutagenesis studies revealed that the catalytic triad of EstU1 plays a crucial role in hydrolyzing both ester bonds of p-nitrophenyl esters and amide bonds of the β-lactam ring of antibiotics, implicating the predicted catalytic triad of EstU1 in both activities.

| S-EPMC3209169 | biostudies-literature

In Vitro Susceptibility of Clinical Staphylococcus aureus Small-Colony Variants to β-Lactam and Non-β-Lactam Antibiotics.

Project description:The Staphylococcus aureus small-colony variant (SCV) phenotype has been associated with relapsing and antibiotic-refractory infections. However, little is known about the activities of antibiotics on clinical SCVs. Here, we demonstrated that SCVs without detectable auxotrophies were at least as susceptible to most β-lactam and non-β-lactam antibiotics in vitro as their corresponding clonally identical strains with a normal phenotype. After prolonged incubation, a regrowth phenomenon has been observed in gradient diffusion inhibition zones irrespective of the strains' phenotype.

| S-EPMC5913952 | biostudies-literature

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