Salmonella enterica Infections Are Disrupted by Two Small Molecules That Accumulate within Phagosomes and Differentially Damage Bacterial Inner Membranes

Villanueva, Joseph A.; Crooks, Amy L.; Nagy, Toni A.; Quintana, Joaquin L. J.; Dalebroux, Zachary D.; Detweiler, Corrella S.

doi:10.1128/mbio.01790-22

Cited by 5 publications

(6 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Along these lines, persister cells and biofilms are both recalcitrant to antibiotics, as are stationary phase bacteria, in comparison to mid-log phase bacteria, potentially due to differences in membrane permeability (48,49). In macrophages, D66 could have activity against pathogens within vesicles in part due to lysosomal trapping of the compound with the acidification of the phagosome (13). Phagosomes that harbor S. aureus also become acidified, and, as with S. Typhimurium, low pH induces virulence gene expression (50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

“…These works have identified compounds that lack antibacterial activity in standard microbiological media but inhibit bacterial growth under broth conditions that mimic the macrophage phagosome environment. For instance, such compounds prevent S. Typhimurium replication in broth in growth media or altered genetic backgrounds that increase outer membrane permeability and/or inactivate efflux pumps (7,9,(11)(12)(13)(14). Thus, the relative impermeability of the Gram-negative cell envelope in standard media complicates study of the mechanism of action for these compounds.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Dombach,

Christensen,

Allgood

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

New molecular approaches to disrupting bacterial infections are needed. The bacterial cell membrane is an essential structure with diverse potential lipid and protein targets for antimicrobials. While rapid lysis of the bacterial cell membrane kills bacteria, lytic compounds are generally toxic to whole animals. In contrast, compounds that subtly damage the bacterial cell membrane could disable a microbe, facilitating pathogen clearance by the immune system with limited compound toxicity. A previously described small molecule, D66, terminates Salmonella enterica serotype Typhimurium (S. Typhimurium) infection of macrophages and reduces tissue colonization in mice. The compound dissipates bacterial inner membrane voltage without rapid cell lysis under broth conditions that permeabilize the outer membrane or disable efflux pumps. In standard media, the cell envelope protects Gram-negative bacteria from D66. We evaluated the activity of D66 in Gram-positive bacteria because their distinct envelope structure, specifically the absence of an outer membrane, could facilitate mechanism of action studies. We observed that D66 inhibited Gram-positive bacterial cell growth, rapidly increased Staphylococcus aureus membrane fluidity, and disrupted membrane voltage while barrier function remained intact. The compound also prevented planktonic staphylococcus from forming biofilms and disturbed three-dimensional structure in one-day-old biofilms. D66 furthermore reduced the survival of staphylococcal persister cells and of intracellular S. aureus. These data indicate that staphylococcal cells in multiple growth states germane to infection are susceptible to changes in lipid packing and membrane conductivity. Thus, agents that subtly damage bacterial cell membranes could have utility in preventing or treating disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Dombach,

Christensen,

Allgood

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Along these lines, persister cells and biofilms are both recalcitrant to antibiotics, as are stationary phase bacteria, in comparison to mid-log phase bacteria, potentially due to differences in membrane permeability ( 48 , 49 ). In macrophages, D66 could have activity against pathogens within vesicles in part due to lysosomal trapping of the compound with the acidification of the phagosome ( 13 ). Phagosomes that harbor S. aureus also become acidified, and, as with S .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of multiple staphylococcal growth states by a small molecule that disrupts membrane fluidity and voltage

Dombach,

Christensen,

Allgood

et al. 2024

mSphere

Self Cite

View full text Add to dashboard Cite

New molecular approaches to disrupting bacterial infections are needed. The bacterial cell membrane is an essential structure with diverse potential lipid and protein targets for antimicrobials. While rapid lysis of the bacterial cell membrane kills bacteria, lytic compounds are generally toxic to whole animals. In contrast, compounds that subtly damage the bacterial cell membrane could disable a microbe, facilitating pathogen clearance by the immune system with limited compound toxicity. A previously described small molecule, D66, terminates Salmonella enterica serotype Typhimurium ( S . Typhimurium) infection of macrophages and reduces tissue colonization in mice. The compound dissipates bacterial inner membrane voltage without rapid cell lysis under broth conditions that permeabilize the outer membrane or disable efflux pumps. In standard media, the cell envelope protects Gram-negative bacteria from D66. We evaluated the activity of D66 in Gram-positive bacteria because their distinct envelope structure, specifically the absence of an outer membrane, could facilitate mechanism of action studies. We observed that D66 inhibited Gram-positive bacterial cell growth, rapidly increased Staphylococcus aureus membrane fluidity, and disrupted membrane voltage while barrier function remained intact. The compound also prevented planktonic staphylococcus from forming biofilms and a disturbed three-dimensional structure in 1-day-old biofilms. D66 furthermore reduced the survival of staphylococcal persister cells and of intracellular S. aureus . These data indicate that staphylococcal cells in multiple growth states germane to infection are susceptible to changes in lipid packing and membrane conductivity. Thus, agents that subtly damage bacterial cell membranes could have utility in preventing or treating disease. IMPORTANCE An underutilized potential antibacterial target is the cell membrane, which supports or associates with approximately half of bacterial proteins and has a phospholipid makeup distinct from mammalian cell membranes. Previously, an experimental small molecule, D66, was shown to subtly damage Gram-negative bacterial cell membranes and to disrupt infection of mammalian cells. Here, we show that D66 increases the fluidity of Gram-positive bacterial cell membranes, dissipates membrane voltage, and inhibits the human pathogen Staphylococcus aureus in several infection-relevant growth states. Thus, compounds that cause membrane damage without lysing cells could be useful for mitigating infections caused by S. aureus .

show abstract

“…After the engulfment, the bacterium is encased in a host-derived sheath of a membrane known as a vacuole (also named a Salmonella-containing vacuole, SCV) (Figure 2A). The host cell then triggers the fusion of the phagosome with lysosomes and the production of enzymes and reactive oxygen species to destroy the captured bacteria [40]. The bacterium injects effector proteins directly into the vacuole using the T3SS, resulting in the compartment's structural modification.…”

Section: Pathogenicity Islandsmentioning

confidence: 99%

Human Salmonellosis: A Continuous Global Threat in the Farm-to-Fork Food Safety Continuum

Al-Hindi

Albiheyri

Alharbi

et al. 2023

Foods

View full text Add to dashboard Cite

Salmonella is one of the most common zoonotic foodborne pathogens and a worldwide public health threat. Salmonella enterica is the most pathogenic among Salmonella species, comprising over 2500 serovars. It causes typhoid fever and gastroenteritis, and the serovars responsible for the later disease are known as non-typhoidal Salmonella (NTS). Salmonella transmission to humans happens along the farm-to-fork continuum via contaminated animal- and plant-derived foods, including poultry, eggs, fish, pork, beef, vegetables, fruits, nuts, and flour. Several virulence factors have been recognized to play a vital role in attaching, invading, and evading the host defense system. These factors include capsule, adhesion proteins, flagella, plasmids, and type III secretion systems that are encoded on the Salmonella pathogenicity islands. The increased global prevalence of NTS serovars in recent years indicates that the control approaches centered on alleviating the food animals’ contamination along the food chain have been unsuccessful. Moreover, the emergence of antibiotic-resistant Salmonella variants suggests a potential food safety crisis. This review summarizes the current state of the knowledge on the nomenclature, microbiological features, virulence factors, and the mechanism of antimicrobial resistance of Salmonella. Furthermore, it provides insights into the pathogenesis and epidemiology of Salmonella infections. The recent outbreaks of salmonellosis reported in different clinical settings and geographical regions, including Africa, the Middle East and North Africa, Latin America, Europe, and the USA in the farm-to-fork continuum, are also highlighted.

show abstract

Salmonella enterica Infections Are Disrupted by Two Small Molecules That Accumulate within Phagosomes and Differentially Damage Bacterial Inner Membranes

Abstract: Innovative strategies for developing new antimicrobials are needed. Combining our knowledge of host-pathogen interactions and relevant drug characteristics has the potential to reveal new approaches to treating infection.

Cited by 5 publications

References 118 publications

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Inhibition of multiple staphylococcal growth states by a small molecule that disrupts membrane fluidity and voltage

Human Salmonellosis: A Continuous Global Threat in the Farm-to-Fork Food Safety Continuum

Contact Info

Product

Resources

About