- Volume 169, Issue 9, 2023
Volume 169, Issue 9, 2023
- Reviews
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Staph wars: the antibiotic pipeline strikes back
More LessAntibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed to the rapid rise of antimicrobial resistance (AMR) globally. Staphylococcus aureus , a major human pathogen, has become synonymous with multidrug resistance and is a leading antimicrobial-resistant pathogen causing significant morbidity and mortality worldwide. This review focuses on (1) the targets of current anti-staphylococcal antibiotics and the specific mechanisms that confirm resistance; (2) an in-depth analysis of recently licensed antibiotics approved for the treatment of S. aureus infections; and (3) an examination of the pre-clinical pipeline of anti-staphylococcal compounds. In addition, we examine the molecular mechanism of action of novel antimicrobials and derivatives of existing classes of antibiotics, collate data on the emergence of resistance to new compounds and provide an overview of key data from clinical trials evaluating anti-staphylococcal compounds. We present several successful cases in the development of alternative forms of existing antibiotics that have activity against multidrug-resistant S. aureus . Pre-clinical antimicrobials show promise, but more focus and funding are required to develop novel classes of compounds that can curtail the spread of and sustainably control antimicrobial-resistant S. aureus infections.
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- Microbial Primer
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Microbial Primer: LuxR-LuxI Quorum Sensing
More LessQuorum sensing is a term describing bacterial cell-to-cell communication systems for monitoring and responding to changes in population density. This primer serves as an introduction to the canonical LuxR-LuxI-type quorum sensing circuits common to many species of Gram-negative bacteria. Quorum sensing can synchronize behaviours across a community. Different species employ quorum sensing strategies to control specific behaviours such as bioluminescence, virulence factor production, secondary metabolite production, and biofilm formation.
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- Microbial Interactions and Communities
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Major distinctions between the two oligopeptide permease systems of Bacillus subtilis with respect to signaling, development and evolutionary divergence
More LessOligopeptide-permeases (Opps) are used by bacteria to import short peptides. In addition to their metabolic benefit, imported short peptides are used in many Gram-positive bacteria as signalling molecules of the RRNPP super-family of quorum-sensing systems, making Opps an integral part of cell–cell communication. In some Gram-positive bacteria there exist multiple Opps and the relative importance of those to RRNPP quorum sensing are not fully clear. Specifically, in Bacillus subtilis , the Gram-positive model species, there exist two homologous oligopeptide permeases named Opp and App. Previous work showed that the App system is mutated in lab strain 168 and its recovery partially complements an Opp mutation for several developmental processes. Yet, the nature of the impact of App on signalling and development in wild-type strains, where both permeases are active was not studied. Here we re-examine the impact of the two permease systems. We find that App has a minor contribution to biofilm formation, surfactin production and phage infection compared to the effect of Opp. This reduced effect is also reflected in its lower ability to import the signals of four different Rap-Phr RRNPP systems. Further analysis of the App system revealed that, unlike Opp, some App genes have undergone horizontal transfer, resulting in two distinct divergent alleles of this system in B. subtilis strains. We found that both alleles were substantially better adapted than the Opp system to import an exogenous RRNPP signal of the Bacillus cereus group PlcR-PapR system. In summary, we find that the App system has only a minor role in signalling but may still be crucial for the import of other peptides.
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- Microbial Physiology, Biochemistry and Metabolism (formerly Physiology and Metabolism)
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Mutation of putative glycosyl transferases PslC and PslI confers susceptibility to antibiotics and leads to drastic reduction in biofilm formation in Pseudomonas aeruginosa
More LessPseudomonas aeruginosa is an opportunistic, multidrug-resistant pathogen capable of adapting to numerous environmental conditions and causing fatal infections in immunocompromised patients. The predominant lifestyle of P. aeruginosa is in the form of biofilms, which are structured communities of bacteria encapsulated in a matrix containing exopolysaccharides, extracellular DNA (eDNA) and proteins. The matrix is impervious to antibiotics, rendering the bacteria tolerant to antimicrobials. P. aeruginosa also produces a plethora of virulence factors such as pyocyanin, rhamnolipids and lipopolysaccharides among others. In this study we present the molecular characterization of pslC and pslI genes, of the exopolysaccharide operon, that code for putative glycosyltransferases. PslC is a 303 amino acid containing putative GT2 glycosyltrasferase, whereas PslI is a 367 aa long protein, possibly functioning as a GT4 glycosyltransferase. Mutation in either of these two genes results in a significant reduction in biofilm biomass with concomitant decline in c-di-GMP levels in the bacterial cells. Moreover, mutation in pslC and pslI dramatically increased susceptibility of P. aeruginosa to tobramycin, colistin and ciprofloxacin. Additionally, these mutations also resulted in an increase in rhamnolipids and pyocyanin formation. We demonstrate that elevated rhamnolipids promote a swarming phenotype in the mutant strains. Together these results highlight the importance of PslC and PslI in the biogenesis of biofilms and their potential as targets for increased antibiotic susceptibility and biofilm inhibition.
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- Microbial Virulence and Pathogenesis
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Recruitment of C4b-binding protein is not a complement evasion strategy employed by Staphylococcus aureus
More LessComplement offers a first line of defence against infection through the opsonization of microbial pathogens, recruitment of professional phagocytes to the infection site and the coordination of inflammatory responses required for the resolution of infection. Staphylococcus aureus is a successful pathogen that has developed multiple mechanisms to thwart host immune responses. Understanding the precise strategies employed by S. aureus to bypass host immunity will be paramount for the development of vaccines and or immunotherapies designed to prevent or limit infection. To gain a better insight into the specific immune evasion mechanisms used by S. aureus we examined the pathogen’s interaction with the soluble complement inhibitor, C4b-binding protein (C4BP). Previous studies indicated that S. aureus recruits C4BP using a specific cell-wall-anchored surface protein and that bound C4BP limits complement deposition on the staphylococcal surface. Using flow-cytometric-based bacterial-protein binding assays we observed no interaction between S. aureus and C4BP. Moreover, we offer a precautionary warning that C4BP isolated from plasma can be co-purified with minute quantities of human IgG, which can distort binding analysis between S. aureus and human-derived proteins. Combined our data indicates that recruitment of C4BP is not a complement evasion strategy employed by S. aureus .
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Characterization of tigurilysin, a novel human CD59-specific cholesterol-dependent cytolysin, reveals a role for host specificity in augmenting toxin activity
More LessCholesterol-dependent cytolysins (CDCs) are a large family of pore-forming toxins, produced by numerous Gram-positive pathogens. CDCs depend on host membrane cholesterol for pore formation; some CDCs also require surface-associated human CD59 (hCD59) for binding, conferring specificity for human cells. We purified a recombinant version of a putative CDC encoded in the genome of Streptococcus oralis subsp . tigurinus , tigurilysin (TGY), and used CRISPR/Cas9 to construct hCD59 knockout (KO) HeLa and JEG-3 cell lines. Cell viability assays with TGY on wild-type and hCD59 KO cells showed that TGY is a hCD59-dependent CDC. Two variants of TGY exist among S. oralis subsp . tigurinus genomes, only one of which is functional. We discovered that a single amino acid change between these two TGY variants determines its activity. Flow cytometry and oligomerization Western blots revealed that the single amino acid difference between the two TGY isoforms disrupts host cell binding and oligomerization. Furthermore, experiments with hCD59 KO cells and cholesterol-depleted cells demonstrated that TGY is fully dependent on both hCD59 and cholesterol for activity, unlike other known hCD59-dependent CDCs. Using full-length CDCs and toxin constructs differing only in the binding domain, we determined that having hCD59 dependence leads to increased lysis efficiency, conferring a potential advantage to organisms producing hCD59-dependent CDCs.
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Volumes and issues
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Volume 170 (2024)
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