Therapeutic potential of isoallolithocholic acid in methicillin-resistant Staphylococcus Aureus peritoneal infection
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DJK-5, an anti-biofilm peptide, increases Staphylococcus aureus sensitivity to colistin killing in co-biofilms with Pseudomonas aeruginosa
Chronic infections represent a significant global health and economic challenge. Biofilms, which are bacterial communities encased in an extracellular polysaccharide matrix, contribute to approximately 80% of these infections. In particular, pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus are frequently co-isolated from the sputum of patients with cystic fibrosis and are commonly found in chronic wound infections. Within biofilms, bacteria demonstrate a remarkable increase in resistance and tolerance to antimicrobial treatment. We investigated the efficacy of combining the last-line antibiotic colistin with a membrane- and stringent stress response-targeting anti-biofilm peptide DJK-5 against co-biofilms comprised of multidrug-resistant P. aeruginosa and methicillin-resistant S. aureus (MRSA). Colistin lacks canonical activity against S. aureus. However, our study revealed that under co-biofilm conditions, the antibiofilm peptide DJK-5 synergized with colistin against S. aureus. Similar enhancement was observed when daptomycin, a cyclic lipopeptide against Gram-positive bacteria, was combined with DJK-5, resulting in increased activity against P. aeruginosa. The combinatorial treatment induced morphological changes in both P. aeruginosa and S. aureus cell shape and size within co-biofilms. Importantly, our findings also demonstrate synergistic activity against both P. aeruginosa and S. aureus in a murine subcutaneous biofilm-like abscess model. In conclusion, combinatorial treatments with colistin or daptomycin and the anti-biofilm peptide DJK-5 show significant potential for targeting co-biofilm infections. These findings offer promising avenues for developing new therapeutic approaches to combat complex chronic infections.
Resistance to linezolid in Staphylococcus aureus by mutation, modification, and acquisition of genes
Linezolid binds to the 50S subunit of the bacterial ribosome, inhibiting bacterial protein synthesis by preventing the formation of the initiation complex. Oxazolidinone antimicrobial drugs represent the last line of defense in treating Staphylococcus aureus infections; thus, resistance to linezolid in S. aureus warrants high priority. This article examines the major mechanisms of resistance to linezolid in S. aureus, which include: mutations in the domain V of 23S rRNA (primarily G2576); chromosomal mutations in the rplC, rplD, and rplV genes (encoding the ribosomal uL3, uL4, and uL22 proteins, respectively); the exogenous acquisition of the methylase encoded by the chloramphenicol-florfenicol resistance (cfr) gene; the endogenous methylation or demethylation of 23S rRNA; the acquisition of optrA and poxtA resistance genes; and the existence of the LmrS multidrug efflux pump. In conclusion, these mechanisms mediate resistance through mutations or modifications to the bacterial target, thereby reducing the affinity of linezolid for the peptidyl transferase center (PTC) binding site or by preventing the binding of linezolid to the PTC through a ribosomal protective effect. The existence of additional, unexplained resistance mechanisms requires further investigation and verification.
Changing epidemiology and antimicrobial susceptibility of bloodstream infections at a Vietnamese infectious diseases hospital (2010–2020)
Bloodstream infection (BSI) poses a global health problem, with diverse organisms and rising antimicrobial resistance (AMR). Here, we characterized trends in BSI prevalence, AMR, and antibiotic use at a Vietnamese infectious diseases hospital from 2010 to 2020. Among 108,303 cultured blood samples, 8.8% were positive, yielding 7995 pathogens. Of 7553 BSI cases, 86.4% were community-acquired. BSI prevalence varied from 17 to 35 cases/1000 admissions/year, highest in HIV/hepatitis wards and patients >60. The in-hospital mortality or hospice discharge outcome was 21.3%. The top three pathogens, E. coli (24%), K. pneumoniae (8.7%) and S. aureus (8.5%) exhibited increasing prevalence and multidrug resistance. Pathogens like Cryptococcus neoformans (8.4%), Talaromyces marneffei (6.7%), and Salmonella enterica (6.5%) declined. E. coli and K. pneumoniae were prevalent in older adults with community-acquired BSIs. Antibiotic use reached 842.6 DOT/1000 PD and significantly reduced after an antibiotic control policy. Enhanced surveillance and antimicrobial stewardship are crucial for managing BSIs in Vietnam.
Severity of neonatal influenza infection is driven by type I interferon and oxidative stress
Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNβ 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNβ induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.
Polymicrobial infection in cystic fibrosis and future perspectives for improving Mycobacterium abscessus drug discovery
Polymicrobial communities inhabit the cystic fibrosis (CF) airway, whereby microbial interactions can occur. One prominent CF pathogen is Mycobacterium abscessus, whose treatment is largely unsuccessful. This creates a need to discover novel antimicrobial agents to treat M. abscessus, however the methods used within antibiotic discovery are typically monomicrobial. This review will discuss this pathogen whilst considering the CF polymicrobial environment, to highlight future perspectives to improve M. abscessus drug discovery.
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