Genomic characterization of two carbapenem-resistant Serratia marcescens isolates causing bacteremia: Emergence of KPC-2-encoding IncR plasmids.

The occurrence and transmission of carbapenemase-producing-Enterobacterales (CPE) on a global scale has become a major issue. Clinical reports are rarely providing information on the genomic and plasmid features of carbapenem-resistant Serratia marcescens. Our objective was to investigate the resistance and transmission dynamics of two carbapenem-resistant S. marcescens that are resistant to carbapenem and have caused bacteremia in China. Blood specimens were taken from two individuals with bacteremia. Multiplex PCR was employed to identify genes that code for carbapenemase. Antimicrobial susceptibility tests and plasmid analysis were conducted on S. marcescens isolates SM768 and SM4145. The genome of SM768 and SM4145 were completely sequenced using NovaSeq 6000-PE150 and PacBio RS II platforms. Antimicrobial resistance genes (ARGs) were predicted using the ResFinder tool. S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and southern blotting were employed to analyze plasmids. Two S. marcescens that produced KPC-2 were identified from bloodstream infections. The antimicrobial susceptibility testing demonstrated that both of the isolates had a resistance to various antibiotics. The whole-genome sequence (WGS) and plasmid analysis revealed the presence of bla KPC-2-bearing IncR plasmids and multiple plasmid-borne antimicrobial resistance genes in the isolates. Our comparative plasmid analysis suggested that the two IncR plasmids identified in this study could be derived from a common ancestor. Our findings revealed the emergence of bla KPC-2-bearing IncR plasmid in China, which could be a hindrance to the transmission of KPC-2-producing S. marcescens in clinical settings.

Switching from membrane disrupting to membrane crossing, an effective strategy in designing antibacterial polypeptide.

Drug-resistant bacterial infections have caused serious threats to human health and call for effective antibacterial agents that have low propensity to induce antimicrobial resistance. Host defense peptide-mimicking peptides are actively explored, among which poly-ß-l-lysine displays potent antibacterial activity but high cytotoxicity due to the helical structure and strong membrane disruption effect. Here, we report an effective strategy to optimize antimicrobial peptides by switching membrane disrupting to membrane penetrating and intracellular targeting by breaking the helical structure using racemic residues. Introducing ß-homo-glycine into poly-ß-lysine effectively reduces the toxicity of resulting poly-ß-peptides and affords the optimal poly-ß-peptide, ßLys50HG50, which shows potent antibacterial activity against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) and MRSA persister cells, excellent biosafety, no antimicrobial resistance, and strong therapeutic potential in both local and systemic MRSA infections. The optimal poly-ß-peptide demonstrates strong therapeutic potential and implies the success of our approach as a generalizable strategy in designing promising antibacterial polypeptides.

Role of internal loop dynamics in antibiotic permeability of outer membrane porins.

Gram-negative bacteria pose a serious public health concern due to resistance to many antibiotics, caused by the low permeability of their outer membrane (OM). Effective antibiotics use porins in the OM to reach the interior of the cell; thus, understanding permeation properties of OM porins is instrumental to rationally develop broad-spectrum antibiotics. A functionally important feature of OM porins is undergoing open-closed transitions that modulate their transport properties. To characterize the molecular basis of these transitions, we performed an extensive set of molecular dynamics (MD) simulations of Escherichia coli OM porin OmpF. Markov-state analysis revealed that large-scale motion of an internal loop, L3, underlies the transition between energetically stable open and closed states. The conformation of L3 is controlled by H bonds between highly conserved acidic residues on the loop and basic residues on the OmpF ß-barrel. Mutation of key residues important for the loop's conformation shifts the equilibrium between open and closed states and regulates translocation of permeants (ions and antibiotics), as observed in the simulations and validated by our whole-cell accumulation assay. Notably, one mutant system G119D, which we find to favor the closed state, has been reported in clinically resistant bacterial strains. Overall, our accumulated ∼200 µs of simulation data (the wild type and mutants) along with experimental assays suggest the involvement of internal loop dynamics in permeability of OM porins and antibiotic resistance in Gram-negative bacteria.

Detection of beta-lactamase-producing Enterobacteriaceae in a veterinary hospital environment / Detecção de Enterobactérias produtoras de beta-lactamases em ambiente hospitalar veterinário

Due to the strong selective pressure resulting from the misuse of antibiotics, the natural process of bacterial resistance has been accelerated, leading to the increasingly constant appearance of multiresistant isolates. The high number of multi-resistant bacteria is a one health problem. Enterobacteriaceae are usually commensal bacteria of the gastrointestinal tract. However, they can cause infections, and the most important resistance characteristic among them is the production of ß-lactamases. This study aimed to identify ESBL-producing Enterobacteriaceae of types of TEM, SHV, and the CTX-Mgroups. To isolate the enterobacteria, swabs were collected by swiping objects that had contact with the patients and professionals, and the water of the hospital environment. Ten collections were carried out, yielding 306 samples, from which 118 enterobacteria were identified: Escherichia coli, Enterobacter spp., Klebsiella spp., Proteus mirabilis, Serratiaspp., and Citrobacter spp. Isolates. The genes TEM and CTX-M, for the production of ß-lactamases, were detected in 12.7% of the 118 enterobacterial isolates. It is very important to know the bacterial population circulating in the veterinary hospital environment and its resistance to antimicrobials so that professionals can take appropriate measures to minimize the risks of transmission, especially from cages and consultation tables. In addition, the correct control of the microbiological quality of the supply water, as well as environmental cleaning procedures, are essential to prevent the transmission of these microorganisms.(AU)

Devido à grande pressão seletiva decorrente do uso indevido de antibióticos, tem se acelerado o processo natural de resistência das bactérias, levando ao aparecimento cada vez mais constante de isolados multirresistentes. O elevado número de bactérias multirresistentes identificadas é um problema da saúde única. As enterobactérias são bactérias geralmente comensais do trato gastrointestinal, entretanto podem causar infecções, e a característica de resistência mais importante entre elas é a produção de ß-lactamases. Buscando caracterizar melhor os microrganismos circulantes e potencialmente causadores de infecções em ambiente hospitalar veterinário, este estudo objetivou identificar as enterobactérias produtoras de ESBL do tipo TEM, SHV e os cinco grupos de CTX-M presentes em isolados circulantes em hospital veterinário. Foi realizada coleta de suabes de arrasto de objetos que entram em contato com os pacientes e com os profissionais que ali trabalham, bem como de água, para a identificação das enterobactérias. Foram realizadas 10 coletas, obtendo-se 306 amostras, dessas, 118 enterobactérias foram identificadas: Escherichia coli, Enterobacter, Klebsiella, Proteus mirabilis, Serratia e Citrobacter. Dentre as enterobactérias identificadas, alguns isolados possuíam genes para a produção de ß-lactamases, do tipo TEM e CTX-M. É de grande importância conhecer a população bacteriana circulante no ambiente hospitalar veterinário, e a sua resistência aos antimicrobianos, para que os profissionais possam tomar medidas apropriadas para minimizar os riscos de transmissão, principalmente a partir de gaiolas e mesas de atendimento. Além disso, o correto controle da qualidade microbiológica da água de abastecimento, bem como dos procedimentos de higienização do ambiente, são fundamentais para evitar a transmissão destes microrganismos.(AU)

A noncanonical chaperone interacts with drug efflux pumps during their assembly into bacterial outer membranes.

Bacteria have membrane-spanning efflux pumps to secrete toxic compounds ranging from heavy metal ions to organic chemicals, including antibiotic drugs. The overall architecture of these efflux pumps is highly conserved: with an inner membrane energy-transducing subunit coupled via an adaptor protein to an outer membrane conduit subunit that enables toxic compounds to be expelled into the environment. Here, we map the distribution of efflux pumps across bacterial lineages to show these proteins are more widespread than previously recognised. Complex phylogenetics support the concept that gene cassettes encoding the subunits for these pumps are commonly acquired by horizontal gene transfer. Using TolC as a model protein, we demonstrate that assembly of conduit subunits into the outer membrane uses the chaperone TAM to physically organise the membrane-embedded staves of the conduit subunit of the efflux pump. The characteristics of this assembly pathway have impact for the acquisition of efflux pumps across bacterial species and for the development of new antimicrobial compounds that inhibit efflux pump function.

The importance of active surveillance of carbapenem-resistant Enterobacterales (CRE) in colonization rates in critically ill patients.

OBJECTIVE: This study aimed to demonstrate the importance of active carbapenem-resistant Enterobacterales (CRE) surveillance and evaluate the prevalence of invasive infections, risk factors, and mortality risk in CRE-colonized patients. METHODS: Retrospective cohort study analyzing 1,920 patients identified using an active CRE surveillance protocol, admitted to an adult intensive care unit in southeastern Brazil from January 2014 to December 2018. RESULTS: There were 297 (15.47%) CRE colonized patients, with one colonized for every six control patients. CRE-colonized patients demonstrated an increased chance of infection (odds ratio [OR] 7.967, p < 0.001). Overall, 20.54% of the colonized patients presented invasive infection (81.96% due to Klebsiella pneumoniae). The colonization and infection ratio demonstrated the important role of the active CRE surveillance protocol. There were identified multiple risk factors for CRE colonization, including long-term mechanical ventilation (OR 1.624, p = 0.019) and previous exposure to aminopenicillins (OR 5.204, p < 0.001), carbapenems (OR 3.703, p = 0.017), cephalosporins (OR 12.036, p < 0.001), and fluoroquinolones (OR 5.238, p = 0.012). The mortality risk was significantly higher among colonized (OR 2.356, p < 0.001) and colonized-infected (OR 2.000, p = 0.009) patients and in those with Enterobacter cloacae colonization (OR 5.173, p < 0,001) and previous aminopenicillins exposure (OR 3.452, p = 0.007). CONCLUSIONS: Early detection of CRE colonization through screening testing proved to be an important tool to control CRE spread. However, observation over the years has shown no effective control of colonization and infection. The prevalence rates of CRE colonization and colonization-infection were high, as were the mortality rates. In conclusion, an active CRE surveillance protocol is essential, but its impact depends on the effective implementation of preventive measures and feedback between team members.

From the soil to the clinic: the impact of microbial secondary metabolites on antibiotic tolerance and resistance.

Secondary metabolites profoundly affect microbial physiology, metabolism and stress responses. Increasing evidence suggests that these molecules can modulate microbial susceptibility to commonly used antibiotics; however, secondary metabolites are typically excluded from standard antimicrobial susceptibility assays. This may in part account for why infections by diverse opportunistic bacteria that produce secondary metabolites often exhibit discrepancies between clinical antimicrobial susceptibility testing results and clinical treatment outcomes. In this Review, we explore which types of secondary metabolite alter antimicrobial susceptibility, as well as how and why this phenomenon occurs. We discuss examples of molecules that opportunistic and enteric pathogens either generate themselves or are exposed to from their neighbours, and the nuanced impacts these molecules can have on tolerance and resistance to certain antibiotics.

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.

Resistance pattern of infected chronic wound isolates and factors associated with bacterial resistance to third generation cephalosporins at Mbarara Regional Referral Hospital, Uganda.

BACKGROUND: The objectives of this study were; (I) to determine the proportion of pathogens isolated from patients with infected chronic wounds in the surgical ward of MRRH that are resistant to the third-generation cephalosporins and (II) to determine the factors associated with resistance to third-generation cephalosporins in the surgical ward of MRRH. METHOD(S): This study was a descriptive analytical survey of bacterial isolates from infected chronic wounds among patients admitted in the surgical ward of MRRH, Uganda. Seventy five (75) study participants were recruited in the study using convenient sampling technique. Bacterial culture and identification was performed using standard microbiology laboratory procedures whereas broth microdilution method was used to establish the susceptibility of the identified pathogens. Data for objective one (1) was summarized as proportions while the categorized variables were analyzed using logistic regression to determine whether they were associated with the resistance patterns. The level of significance was preset at 5% and p-values less than 0.05 were considered statistically significant. RESULTS: Generally, all isolates had complete susceptibility (100%) to Cefoperazone+Sulbactam 2g except 7.1% of proteus spp that were resistant. Of all the bacterial isolates studied, Staphylococcus aureus, Enterobacter agglomerans, providencia spp and pseudomonas earuginosa had complete resistance (100%) to Cefopodoxime 200mg while providencia spp and pseudomomas earuginosa had complete resistance (100%) to Cefixime 400mg and cefotaxime 1g. Finally, higher odds of bacterial resistance to more 2 brands of the third generation cephalosporins were observed among participants who had prior exposure to the third generation cephalosporins (OR, 2.22, 95% CI, 0.80-6.14), comorbidities (OR, 1.76, 95% CI, 0.62-4.96) and those who had more than two hospitalizations in a year (OR, 1.39, 95% CI 0.46-4.25). However, multivariate logistic regression was not performed since no factor was significantly associated with resistance to more than two brands of third generation cephalosporins (p >0.05). CONCLUSION: This study found that cefixime and cefpodoixme had high rates of resistance and should not be used in routine management of infected chronic wounds. In addition, the factors investigated in this study were not significantly associated with bacterial resistance to more than two brands of third generation cephalosporins.

Financial strategies targeting healthcare providers to promote the prudent use of antibiotics: a systematic review of the evidence.

Improving prudent use of antibiotics is one way to limit the spread of antimicrobial resistance (AMR). The objective of this systematic review was to assess the effects of financial strategies targeting healthcare providers on the prudent use of antibiotics. A systematic review of the literature was conducted searching PubMed, Embase and Cochrane databases, and the grey literature. Search terms related to antibacterial agents, drug resistance, financial strategies, and healthcare providers and/or prescribers. Twenty-two articles were included in the review, reporting on capitation and salary reimbursement, cost containment interventions, pay-for-performance initiatives, penalties, and a one-off bonus payment. There was substantial variation in the reported outcomes describing prescribing behaviours, including proportion of patients prescribed antibiotics, antibiotic prescriptions per patient, and number of cases treated with recommended antibiotic therapy. All financial strategies were associated with improvements in the appropriate prescription of antibiotics in the short-term, although the magnitude of observed effects varied across financial strategies. Financial penalties were associated with the greatest decreases in inappropriate antibiotic prescriptions, followed by capitation models and pay-for-performance schemes that paid bonuses upon achievement of performance targets. However, the risk of bias across studies must be noted. Findings point to the viability of financial strategies to promote the prudent use of antibiotics. Measuring the downstream impact of prescriber behaviour changes is key to estimating the true value of such interventions to tackle AMR. Research efforts should continue to build the evidence on causal mechanisms driving provider prescribing patterns for antibiotics and the long-term impact on antibiotic prescriptions.

Na+-Coupled Respiration and Reshaping of Extracellular Polysaccharide Layer Counteract Monensin-Induced Cation Permeability in Prevotella bryantii B14.

Monensin is an ionophore for monovalent cations, which is frequently used to prevent ketosis and to enhance performance in dairy cows. Studies have shown the rumen bacteria Prevotella bryantii B14 being less affected by monensin. The present study aimed to reveal more information about the respective molecular mechanisms in P.bryantii, as there is still a lack of knowledge about defense mechanisms against monensin. Cell growth experiments applying increasing concentrations of monensin and incubations up to 72 h were done. Harvested cells were used for label-free quantitative proteomics, enzyme activity measurements, quantification of intracellular sodium and extracellular glucose concentrations and fluorescence microscopy. Our findings confirmed an active cell growth and fermentation activity of P.bryantii B14 despite monensin concentrations up to 60 µM. An elevated abundance and activity of the Na+-translocating NADH:quinone oxidoreductase counteracted sodium influx caused by monensin. Cell membranes and extracellular polysaccharides were highly influenced by monensin indicated by a reduced number of outer membrane proteins, an increased number of certain glucoside hydrolases and an elevated concentration of extracellular glucose. Thus, a reconstruction of extracellular polysaccharides in P.bryantii in response to monensin is proposed, which is expected to have a negative impact on the substrate binding capacities of this rumen bacterium.

Pore-Forming Toxins During Bacterial Infection: Molecular Mechanisms and Potential Therapeutic Targets.

Bacterial infections are predominantly treated with antibiotics, and resistance to antibiotics is becoming an increasing threat to our health. Pore-forming toxins (PFTs) are virulence factors secreted by many pathogenic bacterial strains, both in acute and chronic infections. They are special membrane-targeting proteins that exert toxic effects by forming pores in the cell membrane. Recent studies have elucidated the structure of PFTs and the detailed molecular mechanisms of their pathogenicity. Here, we discuss recent findings that highlight the regulatory mechanisms and important roles of two types of PFTs, α-PFTs and ß-PFTs, in mediating the virulence of bacteria, and the therapeutic potential of targeting PFTs for antibacterial treatment. Therapeutic strategies based on PFTs are highly specific and may alleviate the issue of increasing resistance to antibiotics.

Cefiderocol: A Review in Serious Gram-Negative Bacterial Infections.

Intravenous cefiderocol (Fetroja®; Fetcroja®) is the first siderophore cephalosporin approved for the treatment of adults with serious Gram-negative bacterial infections. Cefiderocol is stable against all four Ambler classes of ß-lactamases (including metallo-ß-lactamases) and exhibits excellent in vitro activity against many clinically relevant Gram-negative pathogens, including multidrug resistant strains. In randomized, double-blind clinical trials, cefiderocol was noninferior to imipenem/cilastatin for the treatment of complicated urinary tract infections (cUTI) and to meropenem for nosocomial pneumonia. Furthermore, in a pathogen-focused clinical trial in patients with carbapenem-resistant (CR) infections, cefiderocol showed comparable efficacy to best available therapy (BAT), albeit all-cause mortality rate was higher in the cefiderocol arm, the cause of which has not been established. Cefiderocol had a good tolerability and safety profile in clinical trials. Thus cefiderocol is a novel, emerging, useful addition to the current treatment options for adults with susceptible Gram-negative bacterial infections (including cUTI and nosocomial pneumonia) for whom there are limited treatment options.

Infections caused by carbapenem-resistant (CR) Enterobacterales and nonfermenters (such as Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia) are a major global health threat. Cefiderocol, a cephalosporin with activity against CR Enterobacterales and nonfermenters, uses the bacteria's own iron uptake system to gain cell entry, like a Trojan horse. Once inside, the drug disrupts the formation of the bacterial cell wall, killing the bacteria. Cefiderocol is approved for the treatment of serious Gram-negative bacterial infections. In clinical trials, cefiderocol was effective versus carbapenems or best available therapy for complicated urinary tract infections, nosocomial pneumonia and bloodstream infections/sepsis, including those caused by CR bacteria. The drug had a good tolerability and safety profile. Thus, cefiderocol is a useful addition to the current treatment options for adults with cefiderocol-susceptible Gram-negative bacterial infections for whom there are limited treatment options.

Evaluation of Chemical Changes in Laboratory-Induced Colistin-Resistant Klebsiella pneumoniae.

This study evaluates the electrical potential and chemical alterations in laboratory-induced colistin-resistant Klebsiella pneumoniae, as compared to the susceptible strain using spectroscopic analyses. The minimal inhibitory concentration (MIC) of colistin, ζ-potential and chemical composition analysis of K. pneumoniae strains are determined. The results obtained for the K. pneumoniaeCol-R with induced high-level colistin resistance (MIC = 16.0 ± 0.0 mg/L) are compared with the K. pneumoniaeCol-S strain susceptible to colistin (MIC = 0.25 ± 0.0 mg/L). Fourier transform infrared (FTIR) and Raman spectroscopic studies revealed differences in bacterial cell wall structures and lipopolysaccharide (LPS) of K. pneumoniaeCol-R and K. pneumoniaeCol-S strains. In the beginning, we assumed that the obtained results could relate to a negative charge of the bacterial surface and different electrostatic interactions with cationic antibiotic molecules, reducing the affinity of colistin and leading to its lower penetration into K. pneumoniaeCol-R cell. However, no significant differences in the ζ-potential between the K. pneumoniaeCol-R and K. pneumoniaeCol-S strains are noticed. In conclusion, this mechanism is most probably associated with recognisable changes in the chemical composition of the K. pneumoniaeCol-R cell wall (especially in LPS) when compared to the susceptible strain.

Lead metal biosorption and isotherms studies by metal-resistant Bacillus strain MRS-2 bacterium.

In this study, lead (Pb) biosorption studies in aqueous solution were performed with metal-resistant Bacillus strain MRS-2 (ATCC 55674) bacterium which was previously isolated from wastewater plant. It showed minimum inhibition concentration of 300 ppm Pb on the nutrient agar plates. Pb biosorption using MRS-2 bacteria was investigated under different parameters such as pH, temperature, biomass dosage, initial Pb concentration, contact time, and type of biomass by batch experiments. Pb concentration was analyzed through Inductively coupled plasma-optical emission spectrometry. The rate of biosorption (Q) and Pb biosorption capacity (qe ) were calculated for above mentioned parameters. It was observed that Pb precipitates by itself from the solution at pH 2 and 8 or above without bacteria and precipitation did not increase even in the presence of bacteria. The results showed that the highest biosorption rate and biosorption capacity (mg/g) were observed at pH 7, 25°C, 2-h contact time with live bacteria. The highest biosorption rate was observed at 1.5 g/L biomass dose and 5 ppm initial Pb concentration, whereas the highest Pb biosorption capacity was observed at 0.25 g/L biomass dose and 12.5 ppm initial Pb concentration. It was observed that Pb biosorption by live bacteria occurred through adsorption on cell surface. In this study, the biosorption isotherm analysis favored the Langmuir isotherm model indicating monolayer biosorption. This Bacillus strain showed higher Pb biosorption capacity than most of the previously reported Bacillus strains. In conclusion, this study indicates that the Bacillus MRS-2 strain can be used to remove Pb from industrial wastewaters in an ecofriendly approach.

Potential of nanoparticles encapsulated drugs for possible inhibition of the antimicrobial resistance development.

The immune system is a dynamic network of cells and cytokines are the major mediators of immune responses which combat pathogens. Based on the cytokine production, effector T cells differentiate into subsets known as Th1, Th2, Th17, or Treg. This system serves as a barrier to intracellular pathogens, bacterial infections and stimulates the production of reactive oxygen species (ROS), reactive nitrogen intermediates, and nitric oxide, which diffuses across membranes and engulfs intracellular pathogens. Oxidative stress occurs when ROS, reactive nitrogen species (RNS) production, and antioxidant defences become imbalanced. Oxidative stress generated by infected cells produces a substantial amount of free radicals which enables the killing of intracellular pathogens. Intracellular pathogens are exposed to endogenous ROS as part of normal aerobic respiration, also exogenous ROS and RNS are generated by the host immune system in response to infection. Nanoparticles which are designed for drug delivery are capable of trapping the desired drug in the particles which protect the drug from enzymatic degradation in a biological system. The subcellular size of nanoparticles enables higher intracellular uptake of the drug which results in the reduction of the concentration of free drugs reducing their toxic effect. Research on the modulation of immune response and oxidative stress using nanoparticles used to encapsulate drugs has yet to be explored fully. In this review, we illustrate the immune activation and generation of oxidative stress properties which are mediated by nanoparticle encapsulated drug delivery systems which can make the therapy more effective in case of diseases caused by intracellular pathogens.

Selenium Nanomaterials to Combat Antimicrobial Resistance.

The rise of antimicrobial resistance to antibiotics (AMR) as a healthcare crisis has led to a tremendous social and economic impact, whose damage poses a significant threat to future generations. Current treatments either are less effective or result in further acquired resistance. At the same time, several new antimicrobial discovery approaches are expensive, slow, and relatively poorly equipped for translation into the clinical world. Therefore, the use of nanomaterials is presented as a suitable solution. In particular, this review discusses selenium nanoparticles (SeNPs) as one of the most promising therapeutic agents based in the nanoscale to treat infections effectively. This work summarizes the latest advances in the synthesis of SeNPs and their progress as antimicrobial agents using traditional and biogenic approaches. While physiochemical methods produce consistent nanostructures, along with shortened processing procedures and potential for functionalization of designs, green or biogenic synthesis represents a quick, inexpensive, efficient, and eco-friendly approach with more promise for tunability and versatility. In the end, the clinical translation of SeNPs faces various obstacles, including uncertain in vivo safety profiles and mechanisms of action and unclear regulatory frameworks. Nonetheless, the promise possessed by these metalloid nanostructures, along with other nanoparticles in treating bacterial infections and slowing down the AMR crisis, are worth exploring.

A link between pH homeostasis and colistin resistance in bacteria.

Colistin resistance is complex and multifactorial. DbcA is an inner membrane protein belonging to the DedA superfamily required for maintaining extreme colistin resistance of Burkholderia thailandensis. The molecular mechanisms behind this remain unclear. Here, we report that ∆dbcA displays alkaline pH/bicarbonate sensitivity and propose a role of DbcA in extreme colistin resistance of B. thailandensis by maintaining cytoplasmic pH homeostasis. We found that alkaline pH or presence of sodium bicarbonate displays a synergistic effect with colistin against not only extremely colistin resistant species like B. thailandensis and Serratia marcescens, but also a majority of Gram-negative and Gram-positive bacteria tested, suggesting a link between cytoplasmic pH homeostasis and colistin resistance across species. We found that lowering the level of oxygen in the growth media or supplementation of fermentable sugars such as glucose not only alleviated alkaline pH stress, but also increased colistin resistance in most bacteria tested, likely by avoiding cytoplasmic alkalinization. Our observations suggest a previously unreported link between pH, oxygen, and colistin resistance. We propose that maintaining optimal cytoplasmic pH is required for colistin resistance in a majority of bacterial species, consistent with the emerging link between cytoplasmic pH homeostasis and antibiotic resistance.