Biology subjects

Hommes, J. W.

Publications and source records attributed to Hommes, J. W..

3 recordsLinked to original sources

bioRxiv2026

A niche-specific role for ArlRS enables Staphylococcus aureus growth within Kupffer cells

Staphylococcus aureus bloodstream infections cause severe morbidity and mortality despite antibiotic therapy. We previously identified Kupffer cells (KCs) as the primary hepatic macrophages that rapidly clear circulating S. aureus, yet a subset of bacteria survives intracellularly and seeds systemic infection. Here, using spinning-disk intravital and super-resolution microscopy, we show that bacterial two-component system (TCS) signaling is required for intracellular replication within KCs in vivo. A global mutant lacking all non-essential TCSs failed to form intracellular microcolonies, and targeted analysis identified the ArlRS system as specifically required for KC replication. {Delta}arlRS bacteria remained as single non-replicating organisms within KCs, exhibited reduced dissemination and kidney abscess formation, and showed attenuated virulence with improved host survival. Complementation with arlRS restored the wildtype phenotype. Notably, the intracellular replication defect was not observed in primary or cultured macrophages, indicating that ArlRS-dependent replication is highly niche-specific and not reproduced by conventional in vitro models. Furthermore, restricting the KC reservoir with vancomycin treatment after infection further reduced renal infection by {Delta}arlRS bacteria. These findings identify ArlRS as a critical regulator of intracellular replication within KCs and establish the KC intracellular reservoir as a key driver of S. aureus pathogenesis and a potential therapeutic target during bloodstream infection.

microbiology↗

bioRxiv2024

Novel Pentafluorosulfanyl-containing Triclocarban Analogs selectively kill Gram-positive bacteria.

The antibacterial and antibiofilm efficacy of our novel pentafluorosulfanyl-containing triclocarban analogs was explored against seven different Gram-positive and Gram-negative indicator strains. After initial screening, they had bactericidal and bacteriostatic activity against Gram-positive bacteria, especially Staphylococcus aureus and MRSA (methicillin-resistant staphylococcus aureus) in a very low concentration. Our results were compared with the most common antibiotic being used (Ciprofloxacin and Gentamycin); the novel components had significantly better antibacterial and antibiofilm activity in lower concentrations in comparison to the antibiotics. For instance, EBP-59 minimum inhibitory concentration was < 0.0003 mM, while ciprofloxacin 0.08 mM. Further antibacterial activity of novel components was surveyed against 10 clinical antibiotic resistance MRSA isolates. Again, novel components had significantly better antibacterial and antibiofilm activity in comparison with antibiotics. Mechanistic studies have revealed that none of these novel compounds exhibit any effect on the reduced thiol, disrupting iron sulfur clusters, or hydrogen peroxide pathways. Instead, their impact is attributed to the disruption of the Gram-positive bacterial cell membrane. Toxicity and safety testing on tissue cell culture showed promising results for the safety of components to the host.

microbiology↗

bioRxiv2023

PNAG exopolysaccharide eradication gives neutrophils access to Staphylococcus aureus biofilm infections

Staphylococcus aureus (S. aureus) can form biofilms on biotic or abiotic surfaces making biofilm infections a relevant clinical problem. Biofilms can evade immunity and resist antimicrobial treatment, and as such an understanding of biofilm infection in vivo is necessary to inform new therapeutics. Using a mouse model of S. aureus foreign-body skin infection and intravital microscopy, we imaged the interactions between neutrophils and S. aureus biofilm. We observed that neutrophils were separated from bacteria by a biofilm matrix composed of the polysaccharide intercellular adhesin (PIA), an exopolysaccharide chemically designated as poly-N-acetylglucosamine (PNAG) that is produced by enzymatic machinery encoded by the icaADBC operon. Infection with icaADBC-deficient S. aureus strains led to increased neutrophil infiltration and access to bacteria and resulted in full clearance of infection by 7 days. Moreover, enzymatic treatment with PgaB, which hydrolyzes partially deacetylated PNAG, was shown to disaggregate the biofilm giving neutrophils access into the infection site to improve clearance. Taken together, our results show that PNAG shelters S. aureus biofilms from innate host defense, and that targeting the biofilm matrix with glycoside hydrolases is a promising therapeutic avenue to treat S. aureus biofilm infections. Author SummaryStaphylococcus aureus is a major cause of biofilm-associated infections, which pose a major threat to human health. A biofilm is difficult to treat since bacteria are protected from antimicrobials within an extracellular matrix. This study is the first to show that the PgaB enzyme, a glycoside hydrolase, can disrupt the S. aureus biofilm matrix in vivo. Disrupting the biofilm matrix with PgaB gives neutrophils access to bacteria for elimination.

immunology↗