Bacterial Biofilm Infections Research Articles

Copper‐infused zinc porphyrin supramolecular polymersomes for triple synergistic combat against wound bacterial biofilm infections

AbstractBacterial biofilm infections (BBI) on wound surfaces and implants pose a significant clinical challenge due to the impermeable nature of biofilms and obstacles in tissue repair. Traditional photothermal therapy (PTT) or chemodynamic therapy (CDT), whether used alone or in combination, often causes damage to surrounding normal tissues from high operating temperatures or elevated levels of reactive oxygen species, leading to unsatisfactory anti‐biofilm effects. This study introduces a novel copper ions loaded zinc porphyrin polymer vesicle (Cu‐PPS) that employs a triple synergistic approach involving PTT, CDT, and bacterial cuproptosis‐like death (BCD). Cu‐PPS exhibits exceptional photothermal efficiency of 51.06%, promoting the release of copper ions under photothermal stimulation, enhancing CDT and BCD effectiveness, and facilitating mature biofilm clearance and tissue repair. This approach achieves a bactericidal rate exceeding 99% and an anti‐biofilm rate of 93.32% in vitro and also excellent efficacy in treating BBI in vivo. This study presents an innovative therapeutic strategy for combating biofilm infections, addressing the challenges encountered in the clinical management of BBI.

Biofilm infections of endobronchial valves in COPD patients after endoscopic lung volume reduction: a pilot study with FISHseq

Endoscopic lung volume reduction (ELVR) using endobronchial valves (EBV) is a treatment option for a subset of patients with severe chronic obstructive pulmonary disease (COPD), suffering from emphysema and hyperinflation. In this pilot study, we aimed to determine the presence of bacterial biofilm infections on EBV and investigate their involvement in lack of clinical benefits, worsening symptomatology, and increased exacerbations that lead to the decision to remove EBVs. We analyzed ten COPD patients with ELVR who underwent EBV removal. Clinical data were compared to the microbiological findings from conventional EBV culture. In addition, EBV were analyzed by FISHseq, a combination of Fluorescence in situ hybridization (FISH) with PCR and sequencing, for visualization and identification of microorganisms and biofilms. All ten patients presented with clinical symptoms, including pneumonia and recurrent exacerbations. Microbiological cultures from EBV detected several microorganisms in all ten patients. FISHseq showed either mixed or monospecies colonization on the EBV, including oropharyngeal bacterial flora, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus spp., and Fusobacterium sp. On 5/10 EBV, FISHseq visualized biofilms, on 1/10 microbial microcolonies, on 3/10 single microorganisms, and on 1/10 no microorganisms. The results of the study demonstrate the presence of biofilms on EBV for the first time and its potential involvement in increased exacerbations and clinical worsening in patients with ELVR. However, further prospective studies are needed to evaluate the clinical relevance of biofilm formation on EBV and appropriate treatment options to avoid infections in patients with ELVR.

Multifunctional NIR-II nanoplatform for disrupting biofilm and promoting infected wound healing

Healing wounds presents a significant challenge due to bacterial biofilm infections and the inherent drug resistance of these biofilms. This report introduces a multifunctional nanoplatform (NPs) designed to combat wound biofilm infections using NIR-II photothermal therapy. The NPs are self-assembled from amphiphilic polymers (AP) to encapsulate photothermal polymers (PT) through classic electrostatic interactions. Importantly, these NPs are electrically neutral, which enhances their ability to penetrate biofilms effectively. Once inside the biofilm, the NPs achieve complete thermal ablation of the biofilm under NIR-II laser irradiation. Additionally, when exposed to laser and the GSH microenvironment, the NPs exhibit strong photothermal effects and self-degradation capabilities. In vitro tests confirm that the NPs have excellent antibacterial and anti-biofilm properties against methicillin-resistant Staphylococcus aureus (MRSA). In vivo studies demonstrate that the NPs can efficiently clear wound biofilm infections and promote wound healing. Notably, the NPs show superior photothermal effects under NIR-II laser irradiation compared to NIR-I lasers. In summary, the developed NPs serve as an integrated diagnostic and therapeutic nano-antimicrobial agent, offering promising applications for biofilm wound infections and wound healing.

Piezoelectric-Enhanced Nanocatalysts Trigger Neutrophil N1 Polarization against Bacterial Biofilm by Disrupting Redox Homeostasis.

Strategies of manipulating redox signaling molecules to inhibit or activate immune signals have revolutionized therapeutics involving reactive oxygen species (ROS). However, certain diseases with dual resistance barriers to the attacks by both ROS and immune cells, such as bacterial biofilm infections of medical implants, are difficult to eradicate by a single exogenous oxidative stimulus due to the diversity and complexity of the redox species involved. Here, this work demonstrates that metal-organic framework (MOF) nanoparticles capable of disrupting the bacterial ROS-defense system can dismantle bacterial redox resistance and induce potent antimicrobial immune responses in a mouse model of surgical implant infection by simultaneously modulating redox homeostasis and initiating neutrophil N1 polarization in the infection microenvironment. Mechanistically, the piezoelectrically enhanced MOF triggers ROS production by tilting the band structure and acts synergistically with the aurintricarboxylic acid loaded within the MOF, which inhibits the activity of the cystathionine γ-cleaving enzyme. This leads to biofilm structure disruption and antigen exposure through homeostatic imbalance and synergistic activation of neutrophil N1 polarization signals. Thus, this study provides an alternative but promising strategy for the treatment of antibiotic-resistant biofilm infections.

MnO2 nanozyme boosts synergistic photodynamic/photothermal therapy of bacterial biofilm infections

As a near-infrared (NIR) adsorbing dye approved by the FDA, indocyanine green (ICG) can serve as an attractive therapeutic agent to combat biofilm infections through synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) due to its deep-tissue penetration ability. However, ICG usually suffers from photo/thermal instability. Herein, to tackle the issues, bovine serum albumin (BSA) stabilized nanozyme MnO2 (BSA/MnO2) was synthesized by reducing manganese permanganate (KMnO4) with BSA, which was further loaded with ICG and coated with the positively charged hydroxypropyltrimethyl ammonium chloride chitosan (HACC) as the bacterial targeting moiety through noncovalent interactions. The constructed ICG@BSA/MnO2@HACC (IBMH) displays good photodynamic/thermal effects and bacterial targetability, enabling a synergistic PDT/PTT therapy against biofilm-associated infections. Compared with free ICG, IBMH exhibits enhanced photo/thermal stability owing to the O2-generating and photothermal capacities of MnO2, which significantly promotes biofilm phototherapy. Meanwhile, IBMH can effectively achieve anti-inflammatory effect due to the reactive oxygen species (ROS) scavenging capacity of nanozyme MnO2, thereby greatly accelerating wound healing after synergistic PDT/PTT. Both in vitro and in vivo assays solidly demonstrate its satisfactory anti-biofilm and anti-inflammatory effects. Therefore, our research proposes a promising and convenient strategy for developing multifunctional nanozyme for synergistic PDT/PTT of biofilm infection.

Fluorescent Microneedle‐Based Theranostic Patch for Naked‐Eye Monitoring and On‐Demand Photo‐Therapy of Bacterial Biofilm Infections

AbstractThe eradication of recalcitrant bacterial biofilm infections necessitates the development of speedy diagnostics and prompt therapeutics. However, constructing a portable versatile platform that enables in situ monitoring of biofilm infections accompanied by potent antibiofilm activity remains challenging. To address this conundrum, a microneedle theranostic patch (Mn: C/G@MN) is devised by incorporating an innovative biophotonic probe (manganese‐doped carbon dots, Mn: CDs) into methacrylated gelatin for visual monitoring of biofilm infection and on‐demand photo‐therapy. The Mn: C/G@MN patch penetrates the physical barrier of biofilms to track their acidic microenvironment, exhibiting a visualized fluorescence color change (from yellow to turquoise) to enable naked‐eye monitoring of biofilm infection. Furthermore, the Mn: C/G@MN patch can drastically eradicate biofilm on‐demand through the synergy of local hyperthermia and hydroxyl radical (•OH) storm under 808 nm near‐infrared light illumination, enabling the damaging of extracellular polymeric substances (EPS) matrix to disperse biofilms and subsequently kill detached bacteria. Both in vitro and in vivo findings authenticate that biofilm infection monitoring‐and‐treating can be achieved. Moreover, the versatile Mn: C/G@MN patch is conducive to suppressing inflammatory responses, expediting collagen deposition, stimulating angiogenesis, and accelerating biofilm‐infected wound healing. As envisaged, this work highlights the potential of such a versatile platform for application in integrated theranostics for biofilm infection.

Reaction-Induced Self-Assembly of Polymyxin Mitigates Cytotoxicity and Reverses Drug Resistance.

Polymyxins have been regarded as an efficient therapeutic against many life-threatening, multidrug resistant Gram-negative bacterial infections; however, the cytotoxicity and emergence of drug resistance associated with polymyxins have greatly hindered their clinical potential. Herein, the reaction-induced self-assembly (RISA) of polymyxins and natural aldehydes in aqueous solution is presented. The resulting assemblies effectively mask the positively charged nature of polymyxins, reducing their cytotoxicity. Moreover, the representative PMBA4 (composed of polymyxin B (PMB) and (E)-2-heptenal (A4)) assemblies demonstrate enhanced binding to Gram-negative bacterial outer membranes and exhibit multiple antimicrobial mechanisms, including increased membrane permeability, elevated bacterial metabolism, suppression of quorum sensing, reduced ATP synthesis, and potential reduction of bacterial drug resistance. Remarkably, PMBA4 assemblies reverse drug resistance in clinically isolated drug-resistant strains of Gram-negative bacteria, demonstrating exceptional efficacy in preventing and eradicating bacterial biofilms. PMBA4 assemblies efficiently eradicate Gram-negative bacterial biofilm infections in vivo and alleviate inflammatory response. This RISA strategy offers a practical and clinically applicable approach to minimize side effects, reverse drug resistance, and prevent the emergence of resistance associated with free polymyxins.

Noninflammatory 97-amino acid High Mobility Group Box 1 derived polypeptide disrupts and prevents diverse biofilms

Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called 'mB Box-97'. We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration. mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model. Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections. This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.

Accelerated healing of intractable biofilm-infected diabetic wounds by trypsin-loaded quaternized chitosan hydrogels that disrupt extracellular polymeric substances and eradicate bacteria

Complex and stubborn bacterial biofilm infections significantly hinder diabetic wound healing and threaten public health. Therefore, a dressing material that effectively clears biofilms and promotes wound healing is urgently required. Herein, we introduce a novel strategy for simultaneously dispersing extracellular polymeric substances and eradicating drug-resistant bacteria. We prepared an ultrabroad-spectrum and injectable quaternized chitosan (QCS) hydrogel loaded with trypsin, which degrades biofilm extracellular proteins. Increased temperature initiated QCS gelation to form the hydrogel, enabling the sustained release of trypsin and effective adherence of the hydrogel to irregularly shaped wounds. To reproduce clinical scenarios, biofilms formed by a mixture of Staphylococcus aureus (S. aureus), Methicillin-resistant S. aureus, and Pseudomonas aeruginosa were administered to the wounds of rats with streptozotocin-induced diabetes. Under these severe infection conditions, the hydrogel efficiently suppressed inflammation, promoted angiogenesis, and enhanced collagen deposition, resulting in accelerated healing of diabetic wounds. Notably, the hydrogel demonstrates excellent biocompatibility without cytotoxicity. In summary, we present a trypsin-loaded QCS hydrogel with tremendous clinical applications potential for the treatment of chronic infected wounds.

Novel benzothiazole derivatives target the Gac/Rsm two-component system as antibacterial synergists against Pseudomonas aeruginosa infections

The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. Pseudomonas aeruginosa infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, SN12 (IC50 = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations in vitro. In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating P. aeruginosa-derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, SN12 slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that SN12 significantly augmented the antibacterial effects of three widely used antibiotics—tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)—compared with single-dose antibiotic treatments for P. aeruginosa infection in vivo. The findings of this study suggest the potential of SN12 as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.

Development of Clindamycin-Releasing Polyvinyl Alcohol Hydrogel with Self-Healing Property for the Effective Treatment of Biofilm-Infected Wounds.

Self-healing hydrogels have good mechanical strength, can endure greater external force, and have the ability to heal independently, resulting in a strong bond between the wound and the material. Bacterial biofilm infections are life-threatening. Clindamycin (Cly) can be produced in the form of a self-healing hydrogel preparation. It is noteworthy that the antibacterial self-healing hydrogels show great promise as a wound dressing for bacterial biofilm infection. In this study, we developed a polyvinyl alcohol/borax (PVA/B) self-healing hydrogel wound dressing that releases Cly. Four ratios of PVA, B, and Cly were used to make self-healing hydrogels: F1 (4%:0.8%:1%), F2 (4%:1.2%:1%), F3 (1.6%:1%), and F4 (4%:1.6%:0). The results showed that F4 had the best physicochemical properties, including a self-healing duration of 11.81 ± 0.34 min, swelling ratio of 85.99 ± 0.12%, pH value of 7.63 ± 0.32, and drug loading of 98.34 ± 11.47%. The B-O-C cross-linking between PVA and borax caused self-healing, according to FTIR spectra. The F4 formula had a more equal pore structure in the SEM image. The PVA/B-Cly self-healing hydrogel remained stable at 6 ± 2 °C for 28 days throughout the stability test. The Korsmeyer-Peppas model released Cly by Fickian diffusion. In biofilm-infected mouse wounds, PVA/B-Cly enhanced wound healing and re-epithelialization. Our results indicate that the PVA/B-Cly produced in this work has reliable physicochemical properties for biofilm-infected wound therapy.

Designing Fast-Moving Antibacterial Microtorpedoes to Treat Lethal Bacterial Biofilm Infections.

Engineering fast-moving microrobot swarms that can physically disassemble bacterial biofilms and kill the bacteria released from the biofilms is a promising way to combat bacterial biofilm infections. Here, we report electrochemical design of Ag7O8NO3 microtorpedoes with outstanding antibacterial performance and meanwhile capable of moving at speeds of hundreds of body lengths per second in clinically used H2O2 aqueous solutions. These fast-moving antibacterial Ag7O8NO3 microtorpedoes could penetrate into and disintegrate the bacterial biofilms and, in turn, kill the bacteria released from the biofilms. Based on the understanding of the growth behavior of the microtorpedoes, we could fine-tune the morphology of the microtorpedoes to accelerate the moving speed and increase their penetration depth into the biofilms simply via controlling the potential waveforms. We further developed an automatic shaking method to selectively peel off the uniformly structured microtorpedoes from the electrode surface, realizing continuous electrochemical production of the microtorpedoes. Animal experiments proved that the microtorpedo swarms greatly increased the survival rate of the mice infected by lethal biofilms to >90%. We used the electrochemical method to design and massively produce uniformly structured fast-moving antibacterial microtorpedo swarms with application potentials in treatment of lethal bacterial biofilm infections.

Flexible nanoplatform facilitates antibacterial phototherapy by simultaneously enhancing photosensitizer permeation and relieving hypoxia in bacterial biofilms

Antimicrobial phototherapy has gained recognition as a promising approach for addressing bacterial biofilms, however, its effectiveness is often impeded by the robust physical and chemical defenses of the biofilms. Traditional antibacterial nanoplatforms face challenges in breaching the extracellular polymeric substances barrier to efficiently deliver photosensitizers deep into biofilms. Moreover, the prevalent hypoxia within biofilms restricts the success of oxygen-reliant phototherapy. In this study, we engineered a soft mesoporous organosilica nanoplatform (SMONs) by incorporating polyethylene glycol (PEG), catalase (CAT), and indocyanine green (ICG), forming SMONs-PEG-CAT-ICG (SPCI). We compared the antimicrobial efficacy of SPCI with more rigid nanoplatforms. Our results demonstrated that unique flexible mechanical properties of SPCI enable it to navigate through biofilm barriers, markedly enhancing ICG penetration in methicillin-resistant Staphylococcus aureus (MRSA) biofilms. Notably, in a murine subcutaneous MRSA biofilm infection model, SPCI showed superior biofilm penetration and pharmacokinetic benefits over its rigid counterparts. The embedded catalase in SPCI effectively converts excess H2O2 present in infected tissues into O2, alleviating hypoxia and significantly boosting the antibacterial performance of phototherapy. Both in vitro and in vivo experiments confirmed that SPCI surpasses traditional rigid nanoplatforms in overcoming biofilm barriers, offering improved treatment outcomes for infections associated with bacterial biofilms. This study presents a viable strategy for managing bacterial biofilm-induced diseases by leveraging the unique attributes of a soft mesoporous organosilica-based nanoplatform. Statement of significanceThis research introduces an innovative antimicrobial phototherapy soft nanoplatform that overcomes the inherent limitations posed by the protective barriers of bacterial biofilms. By soft nanoplatform with flexible mechanical properties, we enhance the penetration and delivery of photosensitizers into biofilms. The inclusion of catalase within this soft nanoplatform addresses the hypoxia in biofilms by converting hydrogen peroxide into oxygen in infected tissues, thereby amplifying the antibacterial effectiveness of phototherapy. Compared to traditional rigid nanoplatforms, this flexible nanoplatform not only promotes the delivery of therapeutic agents but also sets a new direction for treating bacterial biofilm infections, offering significant implications for future antimicrobial therapies.

A self‐regulated phototheranostic nanosystem with single wavelength‐triggered energy switching and oxygen supply for multimodal synergistic therapy of bacterial biofilm infections

AbstractThe exploration of antibiotic‐independent phototherapy strategies for the treatment of bacterial biofilm infections has gained significant attention. However, efficient eradication of bacterial biofilms remains a challenge. Herein, a self‐regulated phototheranostic nanosystem with single wavelength‐triggered photothermal therapy (PTT)/photodynamic therapy (PDT) transformation and oxygen supply for multimodal synergistic therapy of bacterial biofilm infections is presented. This approach combines a eutectic mixture of natural phase‐change materials (PCMs) and an aggregation‐induced emission (AIE) phototheranostic agent TPA‐ICN to form colloidally stable nanopartcicles (i.e. AIE@PCM NPs). The reversible solid−liquid phase transition of PCMs facilitates the adaptive regulation of the aggregation states of TPA‐ICN, enabling a switch between the energy dissipation pathways for enhanced PDT in solid PCMs or enhanced PTT in liquid PCMs. Additionally, oxygen‐carrying thermoresponsive nanoparticles are also introduced to alleviate the hypoxic microenvironment of biofilms by releasing oxygen upon heating by AIE@PCM NPs with enhanced PTT. The nanosystem exhibits outstanding therapeutic efficacy against bacterial biofilms both in vitro and in vivo, with an antibacterial efficiency of 99.99%. This study utilizes a self‐regulated theranostic nanoplatform with adaptive PTT/PDT transformation via the phase transition of PCMs and heat‐triggered oxygen release, holding great promise in the safe and efficient treatment of bacterial biofilm infections.

Customized Lanthanide Nanobiohybrids for Noninvasive Precise Phototheranostics of Pulmonary Biofilm Infection.

A noninvasive strategy for in situ diagnosis and precise treatment of bacterial biofilm infections is highly anticipated but still a great challenge. Currently, no in vivo biofilm-targeted theranostic agent is available. Herein, we fabricated intelligent theranostic alginate lyase (Aly)-NaNdF4 nanohybrids with a 220 nm sunflower-like structure (NaNdF4@DMS-Aly) through an enrichment-encapsulating strategy, which exhibited excellent photothermal conversion efficiency and the second near-infrared (NIR-II) luminescence. Benefiting from the site-specific targeting and biofilm-responsive Aly release from NaNdF4@DMS-Aly, we not only enabled noninvasive diagnosis but also realized Aly-photothermal synergistic therapy and real-time evaluation of therapeutic effect in mice models with Pseudomonas aeruginosa biofilm-induced pulmonary infection. Furthermore, such nanobiohybrids with a sheddable siliceous shell are capable of delaying the NaNdF4 dissolution and biodegradation upon accomplishing the therapy, which is highly beneficial for the biosafety of theranostic agents.

Antibiotic Augmentation of Thermal Eradication of Staphylococcus epidermidis Biofilm Infections.

Staphylococcus epidermidis is a major contributor to bacterial infections on medical implants, currently treated by surgical removal of the device and the surrounding infected tissue at considerable morbidity and expense. In situ hyperthermia is being investigated as a non-invasive means of mitigating these bacterial biofilm infections, but minimizing damage to the surrounding tissue requires augmenting the thermal shock with other approaches such as antibiotics and discerning the minimum shock required to eliminate the biofilm. S. epidermidis biofilms were systematically shocked at a variety of temperatures (50-80 °C) and durations (1-10 min) to characterize their thermal susceptibility and compare it to other common nosocomial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Biofilms were also exposed to three classes of antibiotics (ciprofloxacin, tobramycin and erythromycin) separately at concentrations ranging from 0 to 128 μg mL-1 to evaluate their impact on the efficacy of thermal shock and the subsequent potential regrowth of the biofilm. S. epidermidis biofilms were shown to be more thermally susceptible to hyperthermia than other common bacterial pathogens. All three antibiotics substantially decreased the duration and/or temperature needed to eliminate the biofilms, though this augmentation did not meet the criteria of synergism immediately following thermal shock. Subsequent reincubation, however, revealed strong synergism on a longer timescale.

Co-spray dried inhalable composite powders of ciprofloxacin and alginate oligosaccharide as anti-biofilm therapy

The treatment of chronic respiratory infections caused by biofilm formation are extremely challenging owing to poor drug penetration into the complex biofilm structure and high drug resistance. Local delivery of an antibiotic together with a non-antibiotic adjuvant to the lungs could often enhance the therapeutic responses by targeting different bacterial growth pathways and minimizing drug resistance. In this study, we designed new inhalable dry powders containing ciprofloxacin (CIP) and OligoG (Oli, a low-molecular-weight alginate oligosaccharide impairing the mucoid biofilms by interacting with their cationic ions) to combat respiratory bacterial biofilm infections. The resulting powders were characterized with respect to their morphology, solid-state property, surface chemistry, moisture sorption behavior, and dissolution rate. The aerosol performance and storage stability of the dry powders were also evaluated. The results showed that inhalable dry powders composed of CIP and Oli could be readily accomplished via the wet milling and spray drying process. Upon the storage under 20 ± 2 °C/20 ± 2 % relative humidity (RH) for one month, there was no significant change in the in vitro aerosol performances of the dry powders. In contrast, the dry powders became non-inhalable following the storage at 20 ± 2 °C/53 ± 2 % RH for one month due to the hygroscopic nature of Oli, which could be largely prevented by incorporation of leucine. Collectively, this study suggests that the newly developed co-spray-dried powders composed of CIP and Oli might represent a promising and alternative treatment strategy against respiratory bacterial biofilm infections.

Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm.

Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin-uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga-CT@P nanocomposites constructed with gallium, copper-doped tetrakis (4-carboxyphenyl) porphyrin (TCPP) metal-organic framework, and polyamine-amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium-incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real-time fluorescent iron-sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga-CT@P nanocomposites induced long-term iron starvation, which affected iron-sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.

Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm

AbstractGiven the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin‐uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga‐CT@P nanocomposites constructed with gallium, copper‐doped tetrakis (4‐carboxyphenyl) porphyrin (TCPP) metal–organic framework, and polyamine‐amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium‐incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a “give and take” approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real‐time fluorescent iron‐sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga‐CT@P nanocomposites induced long‐term iron starvation, which affected iron‐sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.

Beyond antibiotics: CRISPR/Cas9 triumph over biofilm-associated antibiotic resistance infections.

A complex structure known as a biofilm is formed when a variety of bacterial colonies or a single type of cell in a group sticks to a surface. The extracellular polymeric compounds that encase these cells, often consisting of proteins, eDNA, and polysaccharides, exhibit strong antibiotic resistance. Concerns about biofilm in the pharmaceutical industry, public health, and medical fields have sparked a lot of interest, as antibiotic resistance is a unique capacity exhibited by these biofilm-producing bacteria, which increases morbidity and death. Biofilm formation is a complicated process that is controlled by several variables. Insights into the processes to target for the therapy have been gained from multiple attempts to dissect the biofilm formation process. Targeting pathogens within a biofilm is profitable because the bacterial pathogens become considerably more resistant to drugs in the biofilm state. Although biofilm-mediated infections can be lessened using the currently available medications, there has been a lot of focus on the development of new approaches, such as bioinformatics tools, for both treating and preventing the production of biofilms. Technologies such as transcriptomics, metabolomics, nanotherapeutics and proteomics are also used to develop novel anti-biofilm agents. These techniques help to identify small compounds that can be used to inhibit important biofilm regulators. The field of appropriate control strategies to avoid biofilm formation is expanding quickly because of this spurred study. As a result, the current article addresses our current knowledge of how biofilms form, the mechanisms by which bacteria in biofilms resist antibiotics, and cutting-edge treatment approaches for infections caused by biofilms. Furthermore, we have showcased current ongoing research utilizing the CRISPR/Cas9 gene editing system to combat bacterial biofilm infections, particularly those brought on by lethal drug-resistant pathogens, concluded the article with a novel hypothesis and aspirations, and acknowledged certain limitations.