Multidrug-resistant Acinetobacter Baumannii Research Articles

Exploitation of a novel adjuvant for polymyxin B against multidrug-resistant Acinetobacter baumannii.

Although polymyxin has been used as a last-resort antibiotic against resistant bacteria, its use is restricted due to nephrotoxicity and neurotoxicity. While the present antibiotic resistance issue compels clinicians to reconsider polymyxin use in severe illness cases, polymyxin-resistant microorganisms exert an effect. To address the issue of antibiotic resistance, the cycle of developing new antibiotics to counteract emerging resistance must be discontinued. Here we tried to develop novel therapies that do not rely on direct antimicrobial activity and thus do not promote antibiotic resistance. By a high-throughout screening system based on bacterial respiration, chemical compounds accelerating the antimicrobial effects of polymyxin B were screened. In vitro and in vivo tests were performed to validate adjuvanticity. In addition, membrane depolarization and total transcriptome analysis were used to determine molecular mechanisms. PA108, a newly discovered chemical compound, was used to eradicate polymyxin-resistant A. baumannii and three other species in the presence of polymyxin B at concentrations less than the MIC. Since this molecule lacks self-bactericidal action, we hypothesized that PA108 acts as an antibiotic adjuvant, enhancing the antimicrobial activity of polymyxin B against resistant bacteria. At working concentrations, no toxicity was observed in cell lines or mice, although co-treatment with PA108 and polymyxin B increased survival of infected mouse and decreased bacterial loads in organs. Boosting antibiotic efficiency through the use of antibiotic adjuvants holds significant promise for tackling the rise in bacterial antibiotic resistance.

Multidrug-resistant Acinetobacter baumannii in healthcare settings in Africa

The emergence of multidrug-resistant Acinetobacter baumannii is a major concern to healthcare providers and facilities in many parts of the world. This bacterial pathogen is commonly implicated in hospital-acquired infections, particularly in critically ill patients admitted to the intensive care unit (ICU). The extensive use of antibiotics, particularly in ICUs, and the lack of proper infection control interventions in many hospitals have led to an increased emergence of multidrug-resistant A. baumannii. Infections due to multidrug-resistant A. baumannii are associated with prolonged hospital stays and high morbidity and mortality, particularly among hospitalized ICU patients. The lack of antibiotic stewardship programmes in many healthcare facilities has exacerbated the burden of A. baumannii infections in many parts of Africa. This review discusses the prevalence and antibiotic-resistance pattern of the multidrug-resistant A. baumannii, and the possible ways to address or minimise its emergence in healthcare settings in Africa.

Molecular docking and dynamic approach to screen the drug candidate against the Imipenem-resistant CarO porin in Acinetobacter baumannii

The multidrug-resistant Acinetobacter baumannii is an emerging nosocomial pathogen in the healthcare sector. Intrinsic resistance in A. baumannii is a significant problem framing a perfect treatment regimen. Also, this organism showed more resistance towards the carbapenem antibiotics, especially for imipenem and meropenem. The development of carbapenem-resistant Acinetobacter baumannii is mainly due to the alteration or loss of the porin region in the outer membrane. The most well-known porin in Acinetobacter baumannii is CarO (carbapenem-associated outer membrane protein). The CarO protein, which functions as a porin channel for carbapenem inflow, may contribute to carbapenem resistance. The current study identifies a potent drug candidate with a better binding affinity to the carbapenem-resistant outer membrane protein. We investigated the specificity of carbapenems such as imipenem, meropenem, ertapenem, biapenem, doripenem, and fluoroquinolone drugs such as sitafloxacin against the imipenem-resistant CarO protein was demonstrated using the computational approaches molecular docking and dynamic simulation for 50 ns. As a result, the high to low enzyme-ligand complex's binding affinity exhibited a greater binding affinity for ertapenem −7.76 kcal·mol−1 and sitafloxacin −7.75 kcal·mol−1 than biapenem, doripenem, meropenem, and imipenem. The molecular dynamic simulation and the MMPBSA analysis depicted ertapenem −55.431±25.908 kJ/mol and sitafloxacin −47.154 ± 11.052 kJ/mol with better binding affinity and more stability against the imipenem resistant CarO protein when it compared to other antibiotics.

Intranasal immunization with outer membrane vesicles (OMV) protects against airway colonization and systemic infection with Acinetobacter baumannii

The multidrug-resistant bacteria Acinetobacter baumannii is a major cause of hospital-associated infection; a vaccine could significantly reduce this burden. The aim was to develop a clinically relevant model of A. baumannii respiratory tract infection and to test the impact of different immunization routes on protective immunity provided by an outer membrane vesicle (OMV) vaccine. BALB/c mice were intranasally challenged with isolates of oxa23-positive global clone GC2 A. baumannii from the lungs of patients with ventilator-associated pneumonia. Mice were immunized with OMVs by the intramuscular, subcutaneous or intranasal routes; protection was determined by measuring local and systemic bacterial load. Infection with A. baumannii clinical isolates led to a more disseminated infection than the prototype A. baumannii strain ATCC17978; with bacteria detectable in upper and lower airways and the spleen. Intramuscular immunization induced an antibody response but did not protect against bacterial infection. However, intranasal immunization significantly reduced airway colonization and prevented systemic bacterial dissemination. Use of clinically relevant isolates of A. baumannii provides stringent model for vaccine development. Intranasal immunization with OMVs was an effective route for providing protection, demonstrating that local immunity is important in preventing A. baumannii infection.

Genomic Comparative Analysis of Two Multi-Drug Resistance (MDR) Acinetobacter baumannii Clinical Strains Assigned to International Clonal Lineage II Recovered Pre- and Post-COVID-19 Pandemic.

After the emergence of COVID-19, numerous cases of A. baumannii/SARS-CoV-2 co-infection were reported. Whether the co-infecting A. baumannii strains have distinctive characteristics remains unknown. A. baumannii AMA_NO was isolated in 2021 from a patient with COVID-19. AMA166 was isolated from a mini-BAL used on a patient with pneumonia in 2016. Both genomes were similar, but they possessed 337 (AMA_NO) and 93 (AMA166) unique genes that were associated with biofilm formation, flagellar assembly, antibiotic resistance, secretion systems, and other functions. The antibiotic resistance genes were found within mobile genetic elements. While both strains harbored the carbapenemase-coding gene blaOXA-23, only the strain AMA_NO carried blaNDM-1. Representative functions coded for by virulence genes are the synthesis of the outer core of lipooligosaccharide (OCL5), biosynthesis and export of the capsular polysaccharide (KL2 cluster), high-efficiency iron uptake systems (acinetobactin and baumannoferrin), adherence, and quorum sensing. A comparative phylogenetic analysis including 239 additional sequence type (ST) 2 representative genomes showed high similarity to A. baumannii ABBL141. Since the degree of similarity that was observed between A. baumannii AMA_NO and AMA166 is higher than that found among other ST2 strains, we propose that they derive from a unique background based on core-genome phylogeny and comparative genome analysis. Acquisition or shedding of specific genes could increase the ability of A. baumannii to infect patients with COVID-19.

Synergistic Activity of Colistin in Combination with Clofoctol against Colistin Resistant Gram-Negative Pathogens.

Colistin is a bactericidal antibiotic identified decades ago which is active against a number of Gram-negative pathogens. After early elimination from clinical use due to toxicity issues, colistin has been reintroduced as a last-resort treatment for antibiotic-resistant Gram-negative infections lacking other therapeutic options. Inevitably, colistin resistance has emerged among clinical isolates, making the development of colistin adjuvants extremely beneficial. Clofoctol is a synthetic antibiotic active against Gram-positive bacteria, with low toxicity and high tropism for the airways. Interestingly, clofoctol has been found to have multiple biological activities and has been proposed for the treatment of several obstructive lung diseases, including asthma, lung cancer, and SARS-CoV-2 infection. In this study, the activity of clofoctol as a colistin adjuvant was investigated in Gram-negative lung pathogens that are critical for the high prevalence of multidrug-resistant isolates, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Clofoctol potentiated the bactericidal effect of colistin in all tested strains and reduced colistin MICs below the susceptibility breakpoint in nearly all colistin-resistant strains. Overall, this observation supports the development of inhaled clofoctol-colistin formulations for the treatment of difficult-to-treat airway infections caused by Gram-negative pathogens. IMPORTANCE Colistin is used as a last-resort antibiotic against extensively drug-resistant Gram-negative pathogens. However, colistin resistance is on the rise. Clofoctol is an antibiotic used against Gram-positive bacteria, with low toxicity and high penetration and storage in the airways. Here, a strong synergistic activity of the colistin-clofoctol combination against colistin-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii isolates is reported, supporting the development of clofoctol-colistin formulations for the therapy of difficult-to-treat airways infections caused by these Gram-negative pathogens.

Drug Combination of Ciprofloxacin and Polymyxin B for the Treatment of Multidrug-Resistant Acinetobacter baumannii Infections: A Drug Pair Limiting the Development of Resistance.

Polymyxins are considered as last-resort antibiotics to treat infections caused by Acinetobacter baumannii. However, there are increasing reports of resistance in A. baumannii to polymyxins. In this study, inhalable combinational dry powders consisting of ciprofloxacin (CIP) and polymyxin B (PMB) were prepared by spray-drying. The obtained powders were characterized with respect to the particle properties, solid state, in vitro dissolution and in vitro aerosol performance. The antibacterial effect of the combination dry powders against multidrug-resistant A. baumannii was assessed in a time-kill study. Mutants from the time-kill study were further investigated by population analysis profiling, minimum inhibitory concentration testing, and genomic comparisons. Inhalable dry powders consisting of CIP, PMB and their combination showed a fine particle fraction above 30%, an index of robust aerosol performance of inhaled dry powder formulations in the literature. The combination of CIP and PMB exhibited a synergistic antibacterial effect against A. baumannii and suppressed the development of CIP and PMB resistance. Genome analyses revealed only a few genetic differences of 3-6 SNPs between mutants and the progenitor isolate. This study suggests that inhalable spray-dried powders composed of the combination of CIP and PMB is promising for the treatment of respiratory infections caused by A. baumannii, and this combination can enhance the killing efficiency and suppress the development of drug resistance.

The RND Efflux Pump Gene Expression in the Biofilm Formation of Acinetobacter baumannii.

Multidrug resistant (MDR) Acinetobacter baumannii is a critical opportunistic pathogen in healthcare-associated infections (HAI). This is attributed to several factors, including its ability to develop biofilms that can enhance antimicrobial resistance (AMR) in addition to creating an environment for horizontal transfer of antibiotic resistance genes. The role of the efflux pump in biofilm formation is important for studies on alternative treatments for biofilms. One of the significant efflux pump families is the RND efflux pump family, which is common in Gram negative bacteria. The aim is to study the role of the RND efflux pump in biofilm formation by A. baumannii. The biofilm formation potential of thirty-four MDR A. baumannii isolates was evaluated by crystal violet assays. The effect of efflux pump inhibition and activation was studied using the efflux pump inhibitor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and the RND efflux pump substrate levofloxacin (at sub-MIC), respectively. The isolates were genotypically grouped by enterobacterial repetitive intergenic consensus (ERIC) typing and the expression of adeABC, adeFGH, and adeIJK efflux pump genes was measured by qPCR. Overall, 88.2% (30/34) of isolates were biofilm producers (the phenotype was variable including strong and weak producers). Efflux pump inhibition by CCCP reduced the biofilm formation significantly (p < 0.05) in 17.6% (6/34) of some isolates, whereas sub-MICs of the substrate levofloxacin increased biofilm formation in 20.5% (7/34) of other isolates. Overexpression of the three RND efflux pump genes was detected in five out of eleven selected isolates for qPCR with remarkable overexpression in the adeJ gene. No correlation was detected between the biofilm phenotype pattern and the RND efflux pump gene expression in biofilm cells relative to planktonic cells. In conclusion, the role of the RND efflux pumps AdeABC, AdeFGH, and AdeIJK in biofilm formation does not appear to be pivotal and the expression differs according to the genetic background of each strain. Thus, these pumps may not be a promising target for biofilm inhibition.

Horizontal Gene Transfer, Fitness Costs and Mobility Shape the Spread of Antibiotic Resistance Genes into Experimental Populations of Acinetobacter Baylyi.

Horizontal gene transfer (HGT) is important for microbial evolution, but how evolutionary forces shape the frequencies of horizontally transferred genetic variants in the absence of strong selection remains an open question. In this study, we evolve laboratory populations of Acinetobacter baylyi (ADP1) with HGT from two clinically relevant strains of multidrug-resistant Acinetobacter baumannii (AB5075 and A9844). We find that DNA can cross the species barrier, even without strong selection, and despite substantial DNA sequence divergence between the two species. Our results confirm previous findings that HGT can drive the spread of antibiotic resistance genes (ARGs) without selection for that antibiotic, but not for all of the resistance genes present in the donor genome. We quantify the costs and benefits of horizontally transferred variants and use whole population sequencing to track the spread of ARGs from HGT donors into antibiotic-sensitive recipients. We find that even though most ARGs are taken up by populations of A. baylyi, the long-term fate of an individual gene depends both on its fitness cost and on the type of genetic element that carries the gene. Interestingly, we also found that an integron, but not its host plasmid, is able to spread in A. baylyi populations despite its strong deleterious effect. Altogether, our results show how HGT provides an evolutionary advantage to evolving populations by facilitating the spread of non-selected genetic variation including costly ARGs.

The Impact of Multidrug-Resistant Acinetobacter baumannii Infection in Critically Ill Patients with or without COVID-19 Infection.

This is a single-center, retrospective, cohort study aimed to evaluate the clinical outcomes of multi-drug resistance in Acinetobacter baumannii infections (MDR-AB) in intensive care unit (ICU) patients with or without a COVID-19 infection and risk factors for blood stream infection. A total of 170 patients with MDR-AB were enrolled in the study. Of these, 118 (70%) patients were admitted to the ICU due to a COVID-19 infection. Comparing the COVID-19 and non-COVID-19 groups, the use of mechanical ventilation (98.31% vs. 76.92%, p = 0.000), the presence of septic shock (96.61% vs. 82.69%, p = 0.002), and the use of steroid (99.15% vs. 71.15%, p = 0.000) and tocilizumab therapies (33.05% vs. 0%, p = 0.000) were more prevalent and statistically more significant in patients with COVID-19 infections. The average length of the ICU stay (21.2 vs. 28.33, p = 0.0042) was significantly lower in patients with COVID-19 infections. Survival rate was 21.19% for the COVID-19 group and 28.85% for non-COVID-19 group with a p-value = 0.0361. COVID-19 status was associated with significantly higher hazards of death (HR 1.79, CI 95% 1.02-3.15, p = 0.043). Higher SOFAB (15.07 vs. 12.07, p = 0.0032) and the placement of an intravascular device (97.06% vs. 89.71%, p = 0.046) were significantly associated with the development of a bloodstream infection. Our study has shown that critically ill patients with an MDR-AB infection, who were admitted due to a COVID-19 infection, had a higher hazard for death compared to non-COVID-19 infected patients.

Genomic relatedness and dissemination of bla NDM-5 among Acinetobacter baumannii isolated from hospital environments and clinical specimens in Thailand.

Acinetobacter baumannii (A. baumannii) is an important cause of nosocomial infection, especially in intensive care units (ICUs). It has the propensity to tolerate various environments and multiple classes of antibiotics. Our study aimed to characterize the comparative genomes of A. baumannii from hospital environments and clinical isolates. Clinical and environmental A. baumannii isolates were collected from a university hospital. Antibiotic susceptibility testing was performed, antibiotic resistance genes (ARGs) were characterized, and repetitive element palindromic-PCR (rep-PCR) typing was performed. Eight representative A. baumannii isolated from environmental and clinical samples from the same wards were selected for whole-genome sequencing (WGS) using the Illumina platform. A total of 106 A. baumannii isolates were obtained from 312 hospital environmental samples. A high percentage of samples with A. baumannii colonization were detected from AMBU bags (77.9%), followed by bedrails (66.7%) and suction tubes (66.7%). We found that 93.4% of the environmental isolates were multidrug-resistant A. baumannii (MDRAB), and 44.7% were extremely drug-resistant A. baumannii (XDRAB). bla OXA-23 bla NDM, and bla OXA-58 were present in 80.2%, 78.3%, and 0.9% of all isolates, respectively. Sixty-one A. baumannii isolates were collected from patient specimens in the same ward. Among all A. baumannii clinical isolates, MDRAB and XDRAB accounted for 82% and 55.7%, respectively. The most dominant ARGs identified was bla OXA-23 (80.3%), followed by bla NDM (55.7%). The genetic diversity of all isolates using rep-PCR could be divided into 33 genotypes. The genome size of eight A. baumannii ranged from 3.78-4.01 Mb. We found six of eight strains to be bla NDM-5-harboring A. baumannii. Mobile genetic elements (MGEs), such as integron1 (intl1), located upstream of bla NDM-5 were observed. The phylogenomic relationship of the core and pan genomes as well as the single nucleotide polymorphism (SNP) count matrix revealed the genetic similarity of A. baumannii environmental and clinical strains obtained from the same ward. This study confirmed that A. baumannii colonized in hospital environments were the main reservoir of nosocomial infection and provides critical information to guide the control of A. baumannii infection.

Virulence potential of multidrug-resistant Acinetobacter baumannii isolates from COVID-19 patients on mechanical ventilation: The first report from Serbia.

Since the WHO declared the COVID-19 pandemic in March 2020, the disease has spread rapidly leading to overload of the health system and many of the patients infected with SARS-CoV-2 needed to be admitted to the intensive care unit (ICU). Around 10% of patients with the severe manifestation of COVID-19 need noninvasive or invasive mechanical ventilation, which represent a risk factor for Acinetobacter baumannii superinfection. The 64 A. baumannii isolates were recovered from COVID-19 patients admitted to ICU at General Hospital "Dr Laza K. Lazarević" Šabac, Serbia, during the period from December 2020 to February 2021. All patients required mechanical ventilation and mortality rate was 100%. The goal of this study was to evaluate antibiotic resistance profiles and virulence potential of A. baumannii isolates recovered from patients with severe form of COVID-19 who had a need for mechanical ventilation. All tested A. baumannii isolates (n = 64) were sensitive to colistin, while resistant to meropenem, imipenem, gentamicin, tobramycin, and levofloxacin according to the broth microdilution method and MDR phenotype was confirmed. In all tested isolates, representatives of international clone 2 (IC2) classified by multiplex PCR for clonal lineage identification, bla AmpC, bla OXA-51, and bla OXA-23 genes were present, as well as ISAba1 insertion sequence upstream of bla OXA-23. Clonal distribution of one dominant strain was found, but individual strains showed phenotypic differences in the level of antibiotic resistance, biofilm formation, and binding to mucin and motility. According to PFGE, four isolates were sequenced and antibiotic resistance genes as well as virulence factors genes were analyzed in these genomes. The results of this study represent the first report on virulence potential of MDR A. baumannii from hospital in Serbia.

Synthesis and Characterization of DOTAM-Based Sideromycins for Bacterial Imaging and Antimicrobial Therapy.

The rise of antimicrobial resistance, especially in Gram-negative bacteria, calls for novel diagnostics and antibiotics. To efficiently penetrate their double-layered cell membrane, we conjugated the potent antibiotics daptomycin, vancomycin, and sorangicin A to catechol siderophores, which are actively internalized by the bacterial iron uptake machinery. LC-MS/MS uptake measurements of sorangicin derivatives verified that the conjugation led to a 100- to 525-fold enhanced uptake into bacteria compared to the free drug. However, the transfer to the cytosol was insufficient, which explains their lack of antibiotic efficacy. Potent antimicrobial effects were observed for the daptomycin conjugate 7 (∼1 μM) against multidrug-resistant Acinetobacter baumannii. A cyanin-7 label aside the daptomycin warhead furnished the theranostic 13 that retained its antibiotic activity and was also able to label ESKAPE bacteria, as demonstrated by microscopy and fluorescence assays. 13 and the cyanin-7 imaging conjugate 14 were stable in human plasma and had low plasma protein binding and cytotoxicity.

Clinical and microbiological patterns in critically ill patients with catheter-associated UTI: A report from Iran

Catheter-associated urinary tract infections (CAUTIs) are among the most common nosocomial infections with different clinical and microbiological characteristics. We studied these characteristics in critically ill patients. This research was a cross-sectional study conducted on intensive care unit (ICU) patients with CAUTI. Patients' demographic and clinical information and laboratory data, including causative microorganisms and antibiotic susceptibility tests, were recorded and analyzed. Finally, the differences between the patients who survived and died were compared. After reviewing 353 ICU cases, 80 patients with CAUTI were finally included in the study. The mean age was 55.9 ± 19.1 years, 43.7% were male and 56.3% were female. The mean length of infection development since hospitalisation and hospital stay were 14.7 (3-90) and 27.8 (5-98) days, respectively. The most common symptom was fever (80%). The microbiological identification showed that the most isolated microorganisms were Multidrug-resistant (MDR) Enterobacteriaceae (75%), Pseudomonas aeruginosa (8.8%), Gram-positive uropathogens (8.8%) and Acinetobacter baumannii (5%). Fifteen patients (18.8%) died among whom infections with A. baumannii (75%) and P. aeruginosa (57.1%) were associated with more death (p = 0.005). Although A. baumannii and P. aeruginosa can be the most important pathogens for death, MDR Enterobacteriaceae are still a serious concern as causes of CAUTIs.

Glycyrrhetinic acid protects against Multidrug-resistant Acinetobacter baumannii-induced lung epithelial cells injury by regulating inflammation and oxidative stress

Glycyrrhetinic acid (GA) is a bio-effective component of Licorice. The GA is a monomer and the ingredient is an Oleanane-type pentacyclic triterpenes that has been used as a remedy for years. Due to the abuse of antibiotics, people pay attention to the emergence of Multidrug-resistant Acinetobacter baumannii (MDR-AB). As a conditional pathogen, MDR-AB causes severe infection, endangering human lives. Our previous studies found GA played an important role in Yinhua Pinggan, a Chinese medicine. However, whether GA could protect lung epithelium from MDR-AB-induced cell injury was elusive. Herein, we investigated the effects of GA on MDR-AB-infected A549 cells. The results showed GA had slightly antibacterial activity to MDR-AB in the GA (high concentration) but no impact on drug resistance genes. Notwithstanding, GA could reverse MDR-AB-induced cell apoptosis, hampered adhesion and invasion of MDR-AB to cells, and inhibit pro-inflammatory cytokines expression of IL-1β, IL-6, and TNF. Besides, MDR-AB-induced reactive oxygen species, pro-oxidative protein malonaldehyde, and myeloperoxidase of cells were decreased by GA, while antioxidative proteins were recovered, showing antioxidative capacity of GA might play a critical role. The expressions of toll-like receptor (TLRs) - 1, 2, 4, 5, 6, and 9 were increased by MDR-AB infection, while GA reversed the tendency. Interestingly, GA inhibited MDR-AB induced myeloiddifferentiationfactor88 expression (MYD88), one downstream con-factors of TLRs, but no affection on Interferon regulatory Factor 3 (IRF3), the other one, indicating GA inhibited MDR-AB induced cell injury by impact TLR/MYD88 pathway to attenuate inflammation. Altogether, our results demonstrated that GA protects against MDR-AB-induced cell injury through its antioxidative and anti-inflammatory properties, which deserve further study in the future.

Factores asociados a infección por Acinetobacter baumannii multidrogorresistente en unidad de cuidados intensivos. Estudio multicéntrico

To analyze the factors associated with multidrug-resistant Acinetobacter baumannii (MDR-Ab) infection, treated at the intensive care unit (ICU) in the city of Trujillo, northern Peru. Case-control study in which 60 medical records of patients admitted to the ICU from three main hospitals in the city of Trujillo in northern Peru were reviewed, divided according to the presence or absence of multidrug-resistant A. baumannii infection (30 patients per group). The OR of the main postulated associated factors was calculated, then a multivariate analysis was performed. The average age was 60.3 and 46.3 years in patients with and without MDR-Ab respectively, being over 75 years old was significantly associated with MDR-Ab, prolonged ICU stay occurred in 90% of patients with Ab-MDR. MDR (OR: 13.5, p&lt;0.001), hypoalbuminemia predominated in 86.7% of patients with MDR infection (OR: 4.33, p=0.041), 83.3% of patients with MDR-Ab were exposed to a central venous catheter (CVC) (OR:3.82; p=0.049), likewise, all patients had previous antibiotic therapy. Multivariate analysis showed that prolonged ICU stay (p=0.035) and CVC use (p=0.008) were independently associated with MDR-Ab infection. Prolonged stay in the ICU and the use of CVC are factors associated

Prevalence of carbapenemase genes blaOXA-51 and blaOXA23 in multi-drug resistance Acinetobacter baumannii isolated from hospital environment

Prevalence of carbapenemase genes blaOXA-51 and blaOXA23 in multi-drug resistance Acinetobacter baumannii isolated from hospital environment

In Vitro Pharmacokinetics of LL-37 and Oncorhyncin II Combination Against Acinetobacter baumannii

Background: Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most common nosocomial pathogens. Antimicrobial peptides (AMPs) have been introduced as a viable alternative to antibiotics in the treatment of MDR pathogens. Objectives: This study was designed to assess the in vitro pharmacokinetics of the combination of two potent AMPs, LL-37 and oncorhyncin II, against A. baumannii (ATCC19606). Methods: The synthesized genes of oncorhyncin II and LL-37 were introduced into Escherichia coli BL21 as the expression host. The minimum inhibitory concentration (MIC), time-kills, and growth kinetics of these peptides were used to evaluate their antimicrobial efficiencies against A. baumannii (ATCC19606). Results: LL-37 and oncorhyncin II recombinant peptides showed MIC of 30.6 and 95.87 µg/mL against A. baumannii, respectively. Additive action was confirmed by combining the generated AMPs at the checkerboard approach. The combination of LL-37 and oncorhyncin II at 2 × MIC resulted in a rapid drop in log10 CFU/mL of A. baumannii in the time-kill and growth kinetic findings studies. Conclusions: The combination of the produced LL-37 and oncorhyncin II synergizes the bioactivity of the individual peptides. Therefore, these peptides or their combinations might function as novel antibiotics and be used to develop and produce new antimicrobial drugs for the treatment of infections caused by A. baumannii.

Antimicrobial activity of D-amino acid in combination with photo-sonoactivated hypericin nanoparticles against Acinetobacter baumannii

BackgroundThe emergence of multidrug-resistant Acinetobacter baumannii strains is increasing worldwide. To overcome these life-threatening infections, the development of new treatment approaches is critical. For this purpose, this study was conducted to determine the antimicrobial photo-sonodynamic therapy (aPSDT) using hypericin nanoparticles (HypNP) in combination with D-Tryptophan (D-Trp) against A. baumannii.Materials and methodsHypNP was synthesized and characterized, followed by the determination of the fractional inhibitory concentration (FIC) index of HypNP and D-Trp by checkerboard assay. Next, the antimicrobial and anti-biofilm potential of HypNP@D-Trp-mediated aPSDT against A. baumannii was evaluated. Finally, the anti-virulence activity of aPSDT using HypNP@D-Trp was accessed following the characterization of HypNP@D-Trp interaction with AbaI using in silico virtual screening and molecular docking.ResultsA synergistic activity in the combination of HypNP and D-Trp against A. baumannii was observed with a FIC index value of 0.5. There was a 5.10 log10 CFU/mL reduction in the cell viability of A. baumannii when the bacterial cells were treated with 1/2 × MIC of HypNP@D-Trp and subsequently exposed to ultrasound waves and blue light (P < 0.05). Moreover, a significant biofilm degradation effect on biofilm-associated cells of A. baumannii was observed after treatment with aPSDT using 2 × MIC of HypNP@D-Trp in comparison with the control groups (P < 0.05). According to the molecular docking analysis of the protein-ligand complex, Hyp with a high affinity for AbaI showed a binding affinity of − 9.41 kcal/mol. Also, the expression level of abaI gene was significantly downregulated by 10.32-fold in A. baumannii treated with aPSDT as comprised with the control group (P < 0.05).ConclusionsIt can be concluded that HypNP@D-Trp-mediated aPSDT can be considered a promising strategy to overcome the infections caused by A. baumannii by reducing the growth of bacterial biofilm and decreasing the expression of abaI as a gene involved in A. baumannii biofilm formation.

Structure–function correlates of fibrinogen binding by Acinetobacter adhesins critical in catheter-associated urinary tract infections

Multidrug-resistantAcinetobacter baumannii infections are an urgent clinical problem and can cause difficult-to-treat nosocomial infections. During such infections, like catheter-associated urinary tract infections (CAUTI), A. baumannii rely on adhesive, extracellular fibers, called chaperone-usher pathway (CUP) pili for critical binding interactions. The A. baumannii uropathogenic strain, UPAB1, and the pan-European subclone II isolate, ACICU, use the CUP pili Abp1 and Abp2 (previously termed Cup and Prp, respectively) in tandem to establish CAUTIs, specifically to facilitate bacterial adherence and biofilm formation on the implanted catheter. Abp1 and Abp2 pili are tipped with two domain tip adhesins, Abp1D and Abp2D, respectively. We discovered that both adhesins bind fibrinogen, a critical host wound response protein that is released into the bladder upon catheterization and is subsequently deposited on the catheter. The crystal structures of the Abp1D and Abp2D receptor-binding domains were determined and revealed that they both contain a large, distally oriented pocket, which mediates binding to fibrinogen and other glycoproteins. Genetic, biochemical, and biophysical studies revealed that interactions with host proteins are governed by several critical residues in and along the edge of the binding pocket, one of which regulates the structural stability of an anterior loop motif. K34, located outside of the pocket but interacting with the anterior loop, also regulates the binding affinity of the protein. This study illuminates the mechanistic basis of the critical fibrinogen-coated catheter colonization step in A. baumannii CAUTI pathogenesis.