Publications
21 results found
Schrader SM, Botella H, Vaubourgeix J, 2023, Reframing antimicrobial resistance as a continuous spectrum of manifestations, CURRENT OPINION IN MICROBIOLOGY, Vol: 72, ISSN: 1369-5274
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- Citations: 3
Schrader S, Botella H, Jansen R, et al., 2021, Multiform antimicrobial resistance from a metabolic mutation, Science Advances, Vol: 7, Pages: 1-17, ISSN: 2375-2548
A critical challenge for microbiology and medicine is how to cure infections by bacteria that survive antibiotic treatment by persistence or tolerance. Seeking mechanisms behind such high survival, we developed a forward-genetic method for efficient isolation of high24 survival mutants in any culturable bacterial species. We found that perturbation of an essential biosynthetic pathway (arginine biosynthesis) in a mycobacterium generated three distinct forms of resistance to diverse antibiotics, each mediated by induction of WhiB7— high persistence and tolerance to kanamycin, high survival upon exposure to rifampicin, and MIC-shifted resistance to clarithromycin. As little as one base change in a gene encoding a metabolic pathway component conferred multiple forms of resistance to multiple antibiotics with different targets. This extraordinary resilience may help explain how sub31 sterilizing exposure to one antibiotic in a regimen can induce resistance to others and invites development of drugs targeting the mediator of multiform resistance, WhiB7.
Harnagel A, Quezada LL, Park SW, et al., 2021, Nonredundant functions of <i>Mycobacterium tuberculosis</i> chaperones promote survival under stress, MOLECULAR MICROBIOLOGY, Vol: 115, Pages: 272-289, ISSN: 0950-382X
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- Citations: 12
Schrader SM, Vaubourgeix J, Nathan C, 2020, Biology of antimicrobial resistance and approaches to combat it, SCIENCE TRANSLATIONAL MEDICINE, Vol: 12, ISSN: 1946-6234
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- Citations: 73
Wang R, Kreutzfeldt K, Botella H, et al., 2019, Persistent mycobacterium tuberculosis infection in mice requires PerM for successful cell division, eLife, Vol: 8, Pages: 1-21, ISSN: 2050-084X
The ability of Mycobacterium tuberculosis (Mtb) to persist in its host is central to thepathogenesis of tuberculosis, yet the underlying mechanisms remain incompletely defined. PerM,an integral membrane protein, is required for persistence of Mtb in mice. Here, we show that perMdeletion caused a cell division defect specifically during the chronic phase of mouse infection, butdid not affect Mtb’s cell replication during acute infection. We further demonstrate that PerM isrequired for cell division in chronically infected mice and in vitro under host-relevant stressesbecause it is part of the mycobacterial divisome and stabilizes the essential divisome protein FtsB.These data highlight the importance of sustained cell division for Mtb persistence, define conditionspecific requirements for cell division and reveal that survival of Mtb during chronic infectiondepends on a persistence divisome.
Ballinger E, Mosior J, Hartman T, et al., 2019, Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition (vol 363, eaau8959, 2019), SCIENCE, Vol: 364, ISSN: 0036-8075
McKenney PT, Yan J, Vaubourgeix J, et al., 2019, Intestinal bile acids induce a morphotype switch in vancomycin-resistant enterococcus that facilitates intestinal colonization, Cell Host and Microbe, Vol: 25, Pages: 695-705.e5, ISSN: 1931-3128
Vancomycin-resistant Enterococcus (VRE) are highly antibiotic-resistant and readily transmissible pathogens that cause severe infections in hospitalized patients. We discovered that lithocholic acid (LCA), a secondary bile acid prevalent in the cecum and colon of mice and humans, impairs separation of growing VRE diplococci, causing the formation of long chains and increased biofilm formation. Divalent cations reversed this LCA-induced switch to chaining and biofilm formation. Experimental evolution in the presence of LCA yielded mutations in the essential two-component kinase yycG/walK and three-component response regulator liaR that locked VRE in diplococcal mode, impaired biofilm formation, and increased susceptibility to the antibiotic daptomycin. These mutant VRE strains were deficient in host colonization because of their inability to compete with intestinal microbiota. This morphotype switch presents a potential non-bactericidal therapeutic target that may help clear VRE from the intestines of dominated patients, as occurs frequently during hematopoietic stem cell transplantation.
Ballinger E, Mosior J, Hartman T, et al., 2019, Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition, Science, Vol: 363, ISSN: 0036-8075
INTRODUCTIONMycobacterium tuberculosis (Mtb) is the leading global cause of lethal infection in humans and accounts for the largest number of drug-resistant infections by a single bacterial pathogen. Resistance is particularly high against the most widely prescribed tuberculosis (TB) drug, isoniazid. Isoniazid blocks synthesis of mycolates, ultralong-chain fatty acids that provide structure to the waxy coat that surrounds Mtb cells and are incorporated into some of its virulence lipids. There is currently no known method to block the synthesis of both mycolates and nonmycolate-containing virulence lipids of Mtb at a single point of control. One such control point is phosphopantetheinyl transferase (PptT). PptT transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to acyl carrier proteins (ACPs) that synthesize the lipids critical to Mtb structural integrity and virulence.RATIONALETB drug discovery often begins with whole-cell, high-throughput screens that yield compounds that kill Mtb by unknown means. Selection of Mtb mutants resistant to these compounds can indicate candidate targets of the active compound, but experimental validation is required to confirm the functionally relevant target, which is often an enzyme. A suitable target must be essential in vivo, such that its inhibition precludes development of TB in animal models, but also “vulnerable,” meaning that a pharmacologically attainable level of inhibition should be lethal to Mtb within a patient. The inhibitor should act only on Mtb, and resistance should be rare.RESULTSScreening a chemical library revealed an amidino-urea compound called “8918” that kills Mtb, including drug-resistant clinical isolates. 8918 inhibits Mtb in mice and spares other bacteria, yeast, and mammalian cells.Rare Mtb mutants resistant to 8918 bore a point mutation in the PptT gene rv2794c, altering an amino acid residue overlying the Ppt-binding pocket of PptT. When Mtb carried the mutant allel
Botella H, Vaubourgeix J, 2019, Building walls: Work that never ends, Trends in Microbiology, Vol: 27, Pages: 4-7, ISSN: 0966-842X
Fluorescent amino acid analogs have proven to be useful tools for studying the dynamics of peptidoglycan metabolism. García-Heredia and colleagues showed that their route of incorporation differs depending on the adjunct fluorophore and applied this property to investigate mycobacterial peptidoglycan synthesis and remodeling with heightened granularity.
Lupoli TJ, Vaubourgeix J, Burns-Huang K, et al., 2018, Targeting the Proteostasis Network for Discovery, ACS INFECTIOUS DISEASES, Vol: 4, Pages: 478-498, ISSN: 2373-8227
Botella H, Yang G, Ouerfelli O, et al., 2017, Distinct Spatiotemporal Dynamics of Peptidoglycan Synthesis between Mycobacterium smegmatis and Mycobacterium tuberculosis, MBIO, Vol: 8, ISSN: 2150-7511
Botella L, Vaubourgeix J, Livny J, et al., 2017, Depleting Mycobacterium tuberculosis of the transcription termination factor Rho causes pervasive transcription and rapid death, Nature Communications, Vol: 8, Pages: 1-10, ISSN: 2041-1723
Rifampicin, which inhibits bacterial RNA polymerase, provides one of the most effective treatments for tuberculosis. Inhibition of the transcription termination factor Rho is used to treat some bacterial infections, but its importance varies across bacteria. Here we show that Rho of Mycobacterium tuberculosis functions to both define the 3′ ends of mRNAs and silence substantial fragments of the genome. Brief inactivation of Rho affects over 500 transcripts enriched for genes of foreign DNA elements and bacterial virulence factors. Prolonged inactivation of Rho causes extensive pervasive transcription, a genome-wide increase in antisense transcripts, and a rapid loss of viability of replicating and non-replicating M. tuberculosis in vitro and during acute and chronic infection in mice. Collectively, these data suggest that inhibition of Rho may provide an alternative strategy to treat tuberculosis with an efficacy similar to inhibition of RNA polymerase.
Botella H, Vaubourgeix J, Lee MH, et al., 2017, Mycobacterium tuberculosis protease MarP activates a peptidoglycan hydrolase during acid stress, The EMBO Journal, Vol: 36, Pages: 536-548, ISSN: 0261-4189
Mycobacterium tuberculosis (Mtb) can persist in the human host in a latent state for decades, in part because it has the ability to withstand numerous stresses imposed by host immunity. Prior studies have established the essentiality of the periplasmic protease MarP for Mtb to survive in acidified phagosomes and establish and maintain infection in mice. However, the proteolytic substrates of MarP that mediate these phenotypes were unknown. Here, we used biochemical methods coupled with supravital chemical probes that facilitate imaging of nascent peptidoglycan to demonstrate that during acid stress MarP cleaves the peptidoglycan hydrolase RipA, a process required for RipA's activation. Failure of RipA processing in MarP‐deficient cells leads to cell elongation and chain formation, a hallmark of progeny cell separation arrest. Our results suggest that sustaining peptidoglycan hydrolysis, a process required for cell elongation, separation of progeny cells, and cell wall homeostasis in growing cells, may also be essential for Mtb's survival in acidic conditions.
Vaubourgeix J, Lin G, Dhar N, et al., 2015, Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells, Cell Host and Microbe, Vol: 17, Pages: 178-190, ISSN: 1931-3128
Mycobacterium tuberculosis (Mtb) defends itself against host immunity and chemotherapy at several levels, including the repair or degradation of irreversibly oxidized proteins (IOPs). To investigate how Mtb deals with IOPs that can neither be repaired nor degraded, we used new chemical and biochemical probes and improved image analysis algorithms for time-lapse microscopy to reveal a defense against stationary phase stress, oxidants, and antibiotics—the sequestration of IOPs into aggregates in association with the chaperone ClpB, followed by the asymmetric distribution of aggregates within bacteria and between their progeny. Progeny born with minimal IOPs grew faster and better survived a subsequent antibiotic stress than their IOP-burdened sibs. ClpB-deficient Mtb had a marked recovery defect from stationary phase or antibiotic exposure and survived poorly in mice. Treatment of tuberculosis might be assisted by drugs that cripple the pathway by which Mtb buffers, sequesters, and asymmetrically distributes IOPs.
Goodsmith N, Guo XV, Vandal OH, et al., 2015, Disruption of an <i>M</i>. <i>tuberculosis</i> Membrane Protein Causes a Magnesium-dependent Cell Division Defect and Failure to Persist in Mice, PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366
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- Citations: 23
Lin G, Chidawanyika T, Tsu C, et al., 2013, N,C-Capped Dipeptides with Selectivity for Mycobacterial Proteasome over Human Proteasomes: Role of S3 and S1 Binding Pockets, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 135, Pages: 9968-9971, ISSN: 0002-7863
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- Citations: 41
Grzegorzewicz AE, Kordulakova J, Jones V, et al., 2012, A Common Mechanism of Inhibition of the <i>Mycobacterium tuberculosis</i> Mycolic Acid Biosynthetic Pathway by Isoxyl and Thiacetazone, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 38434-38441
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- Citations: 77
Layre E, Cala-De Paepe D, Larrouy-Maumus G, et al., 2011, Deciphering sulfoglycolipids of <i>Mycobacterium tuberculosis</i>, JOURNAL OF LIPID RESEARCH, Vol: 52, Pages: 1098-1110, ISSN: 0022-2275
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- Citations: 37
Jang J, Stella A, Boudou F, et al., 2010, Functional characterization of the <i>Mycobacterium tuberculosis</i> serine/threonine kinase PknJ, MICROBIOLOGY-SGM, Vol: 156, Pages: 1619-1631, ISSN: 1350-0872
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- Citations: 21
Vaubourgeix J, Bardou F, Boissier F, et al., 2009, <i>S</i>-Adenosyl-<i>N</i>-decyl-aminoethyl, a Potent Bisubstrate Inhibitor of <i>Mycobacterium tuberculosis</i> Mycolic Acid Methyltransferases, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 284, Pages: 19321-19330
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- Citations: 24
Peyron P, Vaubourgeix J, Poquet Y, et al., 2008, Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for <i>M-tuberculosis</i> Persistence, PLOS PATHOGENS, Vol: 4, ISSN: 1553-7366
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- Citations: 500
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