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Nature Reviews. Microbiology Mar 2024Burkholderia pseudomallei, the causative agent of melioidosis, is found in soil and water of tropical and subtropical regions globally. Modelled estimates of the global... (Review)
Review
Burkholderia pseudomallei, the causative agent of melioidosis, is found in soil and water of tropical and subtropical regions globally. Modelled estimates of the global burden predict that melioidosis remains vastly under-reported, and a call has been made for it to be recognized as a neglected tropical disease by the World Health Organization. Severe weather events and environmental disturbance are associated with increased case numbers, and it is anticipated that, in some regions, cases will increase in association with climate change. Genomic epidemiological investigations have confirmed B. pseudomallei endemicity in newly recognized regions, including the southern United States. Melioidosis follows environmental exposure to B. pseudomallei and is associated with comorbidities that affect the immune response, such as diabetes, and with socioeconomic disadvantage. Several vaccine candidates are ready for phase I clinical trials. In this Review, we explore the global burden, epidemiology and pathophysiology of B. pseudomallei as well as current diagnostics, treatment recommendations and preventive measures, highlighting research needs and priorities.
Topics: Humans; Burkholderia pseudomallei; Melioidosis; Environmental Exposure; World Health Organization; Genomics
PubMed: 37794173
DOI: 10.1038/s41579-023-00972-5 -
Paediatric Respiratory Reviews Jun 2024Melioidosis is a tropical infectious disease caused by the saprophytic gram-negative bacterium Burkholderia pseudomallei. Despite the infection being endemic in... (Review)
Review
Melioidosis is a tropical infectious disease caused by the saprophytic gram-negative bacterium Burkholderia pseudomallei. Despite the infection being endemic in southeast Asia and northern Australia, the broad clinical presentations and diagnostic difficulties limit its early detection, particularly in children. Melioidosis more commonly affects the immunocompromised and adults. Melioidosis is increasingly being diagnosed around the world and whole-genome sequencing indicates that these cases are not linked with travel to endemic areas. Research has concentrated on the adult population with limited experience reported in the care of this uncommon, but potentially fatal condition in children presenting with bacteraemia and pneumonia.
Topics: Melioidosis; Humans; Child; Burkholderia pseudomallei; Anti-Bacterial Agents; Bacteremia
PubMed: 38245464
DOI: 10.1016/j.prrv.2023.11.002 -
Trends in Microbiology Jan 2024is a Gram negative, facultative intracellular bacterium that resides in the rhizosphere of tropical soils. causes melioidosis, which is transmitted by cutaneous entry,...
is a Gram negative, facultative intracellular bacterium that resides in the rhizosphere of tropical soils. causes melioidosis, which is transmitted by cutaneous entry, ingestion, or inhalation of contaminated soil or water. Infection with can cause a wide array of clinical symptoms such as pneumonia, bone, joint, skin, genitourinary, and central nervous system infections, as well as parotid abscesses in children. Mammalian virulence is linked to the intracellular life cycle, which begins with attachment and internalization by host cells. can infect a wide range of eukaryotic cells, including macrophages, monocytes, and neutrophils, as well as nonphagocytic cells. Once internalized, a type 3 secretion system (T3SS) facilitates escape from the phagosome, and the bacteria replicate in the cytoplasm. Autotransporter protein BimA mediates actin polymerization, enabling to spread, cell to cell, using actin-based motility. This process, coupled with the activity of a type 6 secretion system (T6SS-5), results in host membrane fusion and the formation of multinucleated giant cells. Capsule polysaccharides also contribute to virulence and evasion of host innate immunity. Treatment of infections is complicated by the organism’s intrinsic resistance to multiple classes of antimicrobials, largely due to an abundance of efflux pumps and reduced outer membrane permeability. While is commonly associated with endemic ‘hotspots’ in southeast Asia and northern Australia, there is increasing evidence that it is likely endemic in a large range of tropical and subtropical areas, including regions in Africa, South America, the Middle East, Central America, and the Caribbean. Soil and climate conditions favorable for survival are also found in additional areas worldwide. Consequently, it is important for clinical and public health laboratories located outside of high-endemicity areas to be aware of , as well as for improved diagnostic and reporting methods.
Topics: Burkholderia pseudomallei; Burkholderia
PubMed: 37634974
DOI: 10.1016/j.tim.2023.07.008 -
The American Journal of Tropical... Jun 2023
Topics: Humans; Burkholderia pseudomallei; Melioidosis
PubMed: 37160279
DOI: 10.4269/ajtmh.23-0223 -
Antimicrobial Agents and Chemotherapy Jun 2023Cefiderocol is a siderophore cephalosporin designed mainly for treatment of infections caused by β-lactam and multidrug-resistant Gram-negative bacteria. Burkholderia...
Cefiderocol is a siderophore cephalosporin designed mainly for treatment of infections caused by β-lactam and multidrug-resistant Gram-negative bacteria. Burkholderia pseudomallei clinical isolates are usually highly cefiderocol susceptible, with resistance found in a few isolates. Resistance in clinical B. pseudomallei isolates from Australia is caused by a hitherto uncharacterized mechanism. We show that, like in other Gram-negatives, the PiuA outer membrane receptor plays a major role in cefiderocol nonsusceptibility in isolates from Malaysia.
Topics: Anti-Bacterial Agents; Burkholderia pseudomallei; Gram-Negative Bacteria; Cephalosporins; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests; Cefiderocol
PubMed: 37133377
DOI: 10.1128/aac.00171-23 -
Expert Opinion on Therapeutic Targets 2023Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, α-, β-, γ- and ι-CAs. They play relevant functions related... (Review)
Review
INTRODUCTION
Four different genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) are present in bacteria, α-, β-, γ- and ι-CAs. They play relevant functions related to CO, HCO/H ions homeostasis, being involved in metabolic biosynthetic pathways, pH regulation, and represent virulence and survival factors for bacteria in various niches. Bacterial CAs started to be considered druggable targets in the last decade, as their inhibition impairs survival, growth, and virulence of these pathogens.
AREAS COVERED
Significant advances were registered in the last years for designing effective inhibitors of sulfonamide type for α-CA, α-CA, vacomycin-resistant enterococci (VRE) α- and γ-CAs, for which the in vivo validation has also been achieved. MIC-s in the range of 0.25-4.0 µg/mL for wild type and drug resistant strains, and of 0.007-2.0 µg/mL for VRE were observed for some 1,3,4-thiadiazole-2-sulfonamides, and acetazolamide was effective in gut decolonization from VRE.
EXPERT OPINION
Targeting bacterial CAs from other pathogens, among which , , , serovar Typhimurium, , , , , , , , , , may lead to novel antibacterials devoid of drug resistance problems.
Topics: Humans; Carbonic Anhydrase Inhibitors; Acetazolamide; Sulfonamides; Carbonic Anhydrases; Bacteria; Anti-Bacterial Agents; Sulfanilamide; Structure-Activity Relationship
PubMed: 37747071
DOI: 10.1080/14728222.2023.2263914 -
Journal of Laboratory Physicians Dec 2023The availability of a limited arsenal of antibacterial agents effective against the causative agent of melioidosis, together with sporadic reports of emergence of...
The availability of a limited arsenal of antibacterial agents effective against the causative agent of melioidosis, together with sporadic reports of emergence of resistance necessitates an evaluation of in vitro activity of new antimicrobials against clinical isolates. Cefiderocol (CFDC), a novel siderophore cephalosporin, and ceftazidime-avibactam (CZA), a new β lactam combination agent, have shown promising results for the treatment of difficult-to-treat Gram-negative bacilli infections with limited treatment options. This study was conducted to determine the in vitro activity of CFDC and CZA against a contemporary collection of 60 clinical isolates. Minimum inhibitory concentrations (MIC) of CFDC and CZA were determined by broth microdilution and E-test, respectively. The performance of disk diffusion was also evaluated for CFDC. All isolates were susceptible to CFDC and CZA with MIC range of 0.125 to 2 mg/L and 0.19 to 1 mg/L, respectively. Zone diameters for CFDC ranged from 31 to 40 mm. CFDC and CZA exhibited excellent in vitro activity against 60 isolates. Further pharmacokinetic-pharmacodynamics studies and clinical trials are needed to prove the clinical efficacy of CFDC and CZA in the treatment of melioidosis.
PubMed: 37780886
DOI: 10.1055/s-0043-1770067 -
Communications Biology Sep 2023Burkholderia pseudomallei is a highly versatile pathogen with ~25% of its genome annotated to encode hypothetical proteins. One such hypothetical protein, BPSL1038, is...
Burkholderia pseudomallei is a highly versatile pathogen with ~25% of its genome annotated to encode hypothetical proteins. One such hypothetical protein, BPSL1038, is conserved across seven bacterial genera and 654 Burkholderia spp. Here, we present a 1.55 Å resolution crystal structure of BPSL1038. The overall structure folded into a modified βαββαβα ferredoxin fold similar to known Cas2 nucleases. The Cas2 equivalent catalytic aspartate (D11) pairs are conserved in BPSL1038 although B. pseudomallei has no known CRISPR associated system. Functional analysis revealed that BPSL1038 is a nuclease with endonuclease activity towards double-stranded DNA. The DNase activity is divalent ion independent and optimum at pH 6. The concentration of monovalent ions (Na and K) is crucial for nuclease activity. An active site with a unique D(X20)SST motif was identified and proposed for BPSL1038 and its orthologs. Structure modelling indicates the catalytic role of the D(X20)SST motif and that the arginine residues R10 and R30 may interact with the nucleic acid backbone. The structural similarity of BPSL1038 to Cas2 proteins suggests that BPSL1038 may represent a sub-family of nucleases that share a common ancestor with Cas2.
Topics: Burkholderia pseudomallei; Arginine; Aspartic Acid; Catalysis; Endonucleases
PubMed: 37684342
DOI: 10.1038/s42003-023-05265-4