Anti-virulence therapeutic strategies against bacterial infections: recent advances

Dehbanipour, Razieh; Ghalavand, Zohreh

doi:10.18683/germs.2022.1328

Cited by 52 publications

(21 citation statements)

References 90 publications

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“…Among them, the antivirulence strategy aims to play a distinctive role by interfering with toxin production and virulence factor secretion by bacteria, preventing bacteria from adhering to host cells and forming biofilms, interrupting or inhibiting bacterial communication, or downregulating virulence (18,19). Currently, there are dozens of related research projects at various stages ranging from preclinical studies to clinical trials (20,21).…”

Section: Discussionmentioning

confidence: 99%

A peptide targeting outer membrane protein A ofAcinetobacter baumanniiexhibits antibacterial activity by reducing bacterial pathogenicity

Zhao,

Hu,

Nie

et al. 2024

Preprint

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The World Health Organization has classified multidrug-resistant (MDR) Acinetobacter baumannii as a significant threat to human health, necessitating the urgent discovery of new antibacterial drugs to combat bacterial resistance. Outer membrane protein A of A. baumannii (AbOmpA) is an outer membrane-anchored β?barrel-shaped pore protein that plays a critical role in bacterial adhesion, invasion, and biofilm formation. Therefore, AbOmpA is considered a key virulence factor of A. baumannii. Herein, we screened three phage display peptide libraries targeting AbOmpA and identified several peptides. Among them, P92 (amino acid sequence: QMGFMTSPKHSV) exhibited the highest binding affinity with AbOmpA, with a KD value of 7.84 nM. In vitro studies demonstrated that while P92 did not directly inhibit bacterial growth, it significantly reduced the invasion and adhesion capabilities of multiple clinical isolates of MDR A. baumannii and concentration-dependently inhibited biofilm formation by acting on OmpA. Furthermore, the polymerase chain reaction results confirmed a significant positive correlation between the antibacterial effect of P92 and OmpA expression levels. Encouragingly, P92 also displayed remarkable therapeutic efficacy against A. baumannii infection in various models, including an in vitro cell infection model, a mouse skin infection model, and a mouse sepsis model. These results highlight P92 as a novel and highly effective antimicrobial molecule specifically targeting the virulence factor AbOmpA.

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Section: Discussionmentioning

confidence: 99%

A peptide targeting outer membrane protein A ofAcinetobacter baumanniiexhibits antibacterial activity by reducing bacterial pathogenicity

Zhao,

Hu,

Nie

et al. 2024

Preprint

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“…An emerging idea in bacteriology is therapeutics that block virulence factors, so called anti-virulence drugs. These novel strategies are proposed to reduce the selective pressure, since bacteria are not directly killed, and alleviate the problem of antibiotic resistance (Dehbanipour and Ghalavand 2022). Indeed, substances that target the Type III secretion system (Sharma, Elofsson, and Roy 2020) or effector secretion (Aburto-Rodríguez et al 2021) have been identified.…”

Section: Discussionmentioning

confidence: 99%

The SUbventral-Gland master Regulator (SUGR) of nematode virulence

Pellegrin,

Damm,

Sperling

et al. 2024

Preprint

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All pathogens must tailor their gene expression to their environment. Therefore, targeting host:parasite biology that regulates these changes in gene expression could open up routes to pathogen control. Here, we show that in the plant-parasitic nematode Heterodera schachtii, host signals (termed effectostimulins) within plant roots activate the master regulator sugr1. SUGR1, then, directly binds effector promoters, and orchestrates their production. Effector production, in turn, facilitates host entry, releasing more effectostimulins. These data show that gene expression during the very earliest stages of parasitism is defined by a feed forward loop for host entry. Importantly, we demonstrate that blocking SUGR1 blocks parasitism, underlining the SUGR1 signalling cascade as a valuable target for crop protection. Given that nematodes also parasitise humans and other animals, the potential impact is broad: disrupting effector production could, in principle, be applied to any pathogen that secrets effectors.

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“…IWP-2 was shown to enable lysosomal L. monocytogenes clearance from spacious replication vacuoles in infected macrophages [33]. More recently, PS900, a second generation highly substituted ring-fused 2-pyridone compound, has been shown to not only inhibit PrfA but to disrupt L. monocytogenes ’ general efflux [34].…”

Section: Discussionmentioning

confidence: 99%

“…The C-terminal domain is an α/β domain and bears the Helix-Loop-Helix (HLH) motif that directly interacts with the PrfA boxes scattered across L. monocytogenes' genome [29]. In recent years, several synthetic small molecule PrfA inhibitors have been identified and characterized in detail, such as C01, C16 (Figure 1C), IWP-2 and PS900 among others [31][32][33][34]. These molecules, which bear a ring-fused 2-pyridone scaffold, are considered competitive inhibitors of GST.…”

Section: Introductionmentioning

confidence: 99%

Targeting PrfA from Listeria monocytogenes: a computational drug repurposing approach

Arias Moreno

2023

Preprint

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Humans can develop listeriosis by ingestion of foods contaminated withListeria monocytogenes,an opportunistic gram-positive ubiquitous bacterium. Whilst the non-invasive form of listeriosis may be asymptomatic or cause mild flu-like symptoms, the invasive form of listeriosis is life-threatening and is associated with high hospitalization and fatality rates. Current antibiotic-based therapies are still effective against listeriosis. However, multi-drug resistantListeria monocytogenesstrains have already been identified, which represents a new risk in the treatment of invasive listeriosis. Therefore, it is increasingly urgent to identify new compounds that do not target the conventional biochemical pathways disrupted by current antibiotics. Positive Regulatory Factor A (PrfA) is a well-studied transcriptional factor inListeria monocytogenesthat is responsible for activating a plethora of virulence factors. Targeting virulence factors is a promising strategy that is being considered to combat bacterial infections, hence targeting PrfA is both logical and attractive. In the present computational drug repurposing approach, a complete FDA-approved drugs dataset of more than 700 compounds was virtually screened by docking the drugs against the structure of PrfA. Three of the most promising top-scored FDA drug candidates were then simulated complexed to PrfA. Data from Molecular docking and Molecular Dynamics simulations suggest that Dutasteride and Solifenacin may bind PrfA, and as a result, might exhibit inhibitory activity againstListeria monocytogenes. The use of Dutasteride and Solifenacin is safe in humans since they have been used in the treatment of benign prostatic hyperplasia and androgenic alopecia, and urinary incontinence respectively for decades. Their unique chemical scaffolds may represent valuable starting points for the rapid development of disruptive novel listeria-specific drugs that will be soon needed to combat multi-drug resistantListeria monocytogenesstrains.

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Anti-virulence therapeutic strategies against bacterial infections: recent advances

Cited by 52 publications

References 90 publications

A peptide targeting outer membrane protein A ofAcinetobacter baumanniiexhibits antibacterial activity by reducing bacterial pathogenicity

A peptide targeting outer membrane protein A ofAcinetobacter baumanniiexhibits antibacterial activity by reducing bacterial pathogenicity

The SUbventral-Gland master Regulator (SUGR) of nematode virulence

Targeting PrfA from Listeria monocytogenes: a computational drug repurposing approach

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