Targeting virulence: can we make evolution-proof drugs?

Allen, Richard C.; Popat, Roman; Diggle, Stephen P.; Brown, Sam P.

doi:10.1038/nrmicro3232

Cited by 451 publications

(446 citation statements)

References 103 publications

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“…Potential conflicts with the host‐associated lysogenic phages might lead to unexpected treatment outcomes, and care should be taken to select lytic phage species that do not favor virulent QS‐signaling strains. Furthermore, if phage resistance is positively correlated with functional QS systems, phage therapy could be potentially combined with antivirulence strategies that impair bacterial QS (Allen, Popat, Diggle, & Brown, 2014). Lastly, our results suggest that phage selection might indirectly affect the evolution of social interactions with bacteria by potentially changing the relative benefit of cooperation and cheating.…”

Section: Discussionmentioning

confidence: 99%

Bacterial cell‐to‐cell signaling promotes the evolution of resistance to parasitic bacteriophages

Moreau

Diggle

Friman

2017

Ecology and Evolution

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The evolution of host–parasite interactions could be affected by intraspecies variation between different host and parasite genotypes. Here we studied how bacterial host cell‐to‐cell signaling affects the interaction with parasites using two bacteria‐specific viruses (bacteriophages) and the host bacterium Pseudomonas aeruginosa that communicates by secreting and responding to quorum sensing (QS) signal molecules. We found that a QS‐signaling proficient strain was able to evolve higher levels of resistance to phages during a short‐term selection experiment. This was unlikely driven by demographic effects (mutation supply and encounter rates), as nonsignaling strains reached higher population densities in the absence of phages in our selective environment. Instead, the evolved nonsignaling strains suffered relatively higher growth reduction in the absence of the phage, which could have constrained the phage resistance evolution. Complementation experiments with synthetic signal molecules showed that the Pseudomonas quinolone signal (PQS) improved the growth of nonsignaling bacteria in the presence of a phage, while the activation of las and rhl quorum sensing systems had no effect. Together, these results suggest that QS‐signaling can promote the evolution of phage resistance and that the loss of QS‐signaling could be costly in the presence of phages. Phage–bacteria interactions could therefore indirectly shape the evolution of intraspecies social interactions and PQS‐mediated virulence in P. aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Bacterial cell‐to‐cell signaling promotes the evolution of resistance to parasitic bacteriophages

Moreau

Diggle

Friman

2017

Ecology and Evolution

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“…A worldwide increase in microbial drug resistance, coupled with stagnant growth in the discovery of new antibiotics, underscores the need for novel therapeutic approaches to directly target pathogenesis (35)(36)(37). The IpaH family, with its high conservation across numerous pathogenic Gram-negative bacteria, is an attractive candidate for the development of mechanism-based inhibitors with possibly broad applicability (18).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of catalysis, E2 recognition, and autoinhibition for the IpaH family of bacterial E3 ubiquitin ligases

Keszei

Sicheri

2017

Proc. Natl. Acad. Sci. U.S.A.

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IpaH enzymes are secreted bacterial effectors that function within host cells as E3 ubiquitin (Ub) ligases. Catalytic activity is imparted by a conserved novel E3 ligase (NEL) domain that is unique to Gram-negative pathogens and whose activity is repressed by a flanking substrate-binding leucine-rich repeat (LRR) domain when substrate is absent. How the NEL domain catalyzes the conjugation of Ub onto substrates, recognizes host E2s, and maintains its autoinhibited state remain poorly understood. Here we used mutagenesis and enzyme kinetic analyses to address these gaps in knowledge. Mutagenesis of conserved residues on two remote surfaces of the NEL domain identified functional clusters proximal to and distal to the active site cysteine. By analyzing the kinetics of Ub charging and discharging, we identified proximal active site residues that function as either the catalytic acid or catalytic base for aminolysis. Further analysis revealed that distal site residues mediate the direct binding of E2. In studying the full-length protein, we also have uncovered that IpaH family autoinhibition is achieved by a short-circuiting mechanism wherein the LRR domain selectively blocks productive aminolysis, but not the nonproductive discharge of Ub from the E3 to solvent. This mode of autoinhibition, which is not shared by the HECT domain ligase Smurf2, leads to the unanticipated depletion of E2∼Ub and thus a concomitant dominant-negative effect on other E3s in vitro, raising the possibility that short circuiting also may serve to restrict the function of host E3s in cells.IpaH family | bacterial E3 ubiquitin ligase | ubiquitin | host-pathogen P osttranslational modification by the covalent attachment of the small protein ubiquitin (Ub) onto lysine side chains of target proteins is an essential eukaryotic modification that imparts a wide range of consequences to the substrate, from targeting to the proteasome for degradation to the assembly of signaling complexes (1, 2). Ubiquitination begins with an E1 enzyme, which activates Ub through the consumption of ATP to form a thioester E1∼Ub adduct on its catalytic cysteine. The E1∼Ub conjugate then transthiolates Ub to the active-site cysteine of an E2 enzyme to form an E2∼Ub adduct. Finally, the charged E2∼Ub then collaborates with a diverse group of E3 ligases to catalyze the stable attachment of Ub to the e-amino group of side-chain lysine residues or, in some cases, the N-terminal amino group of protein substrates via an aminolysis reaction.E3 ligases can be divided into two groups based on whether or not they use a catalytic cysteine to form an E3∼Ub intermediate. The HECT (homologous to E6AP C-terminus), RBR (RING-inbetween-RING), and IpaH (invasion-plasmid antigen H) families of structurally distinct E3 ligases use a catalytic cysteine residue to accept activated Ub in the form of an E3∼Ub thioester adduct. The E3 itself then catalyzes the aminolysis reaction to form an isopeptide bond between Ub and the acceptor lysine substrate. In contrast, the RING (really interesting ...

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“…Critically, variation in disease that is due to G parasite Â G parasite may be more amenable to intervention than variation caused by host genotypic differences. Capitalizing on within-host selection is a major tenet of Hamiltonian medicine [106] and understanding how parasite traits influence parasite fitness across spatial scales is crucial to predicting when novel therapies, such as targeting virulence factors, will be successful [107,108].…”

Section: Implications Of Within-host Competition To Host Healthmentioning

confidence: 99%

Within-host competitive interactions as a mechanism for the maintenance of parasite diversity

Bashey

2015

Phil. Trans. R. Soc. B

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Variation among parasite strains can affect the progression of disease or the effectiveness of treatment. What maintains parasite diversity? Here I argue that competition among parasites within the host is a major cause of variation among parasites. The competitive environment within the host can vary depending on the parasite genotypes present. For example, parasite strategies that target specific competitors, such as bacteriocins, are dependent on the presence and susceptibility of those competitors for success. Accordingly, which parasite traits are favoured by within-host selection can vary from host to host. Given the fluctuating fitness landscape across hosts, genotype by genotype (G×G) interactions among parasites should be prevalent. Moreover, selection should vary in a frequency-dependent manner, as attacking genotypes select for resistance and genotypes producing public goods select for cheaters. I review competitive coexistence theory with regard to parasites and highlight a few key examples where within-host competition promotes diversity. Finally, I discuss how within-host competition affects host health and our ability to successfully treat infectious diseases.

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Targeting virulence: can we make evolution-proof drugs?

Cited by 451 publications

References 103 publications

Bacterial cell‐to‐cell signaling promotes the evolution of resistance to parasitic bacteriophages

Bacterial cell‐to‐cell signaling promotes the evolution of resistance to parasitic bacteriophages

Mechanism of catalysis, E2 recognition, and autoinhibition for the IpaH family of bacterial E3 ubiquitin ligases

Within-host competitive interactions as a mechanism for the maintenance of parasite diversity

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