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Potential Tamoxifen Repurposing to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli.

ABSTRACT: The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60-100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections.

SUBMITTER: Miro-Canturri A

PROVIDER: S-EPMC8230278 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The global threat to public health posed by emerging multidrug-resistant bacteria in the past few years necessitates the development of novel approaches to combat bacterial infections. Endolysins encoded by bacterial viruses (or phages) represent one promising avenue of investigation. These enzyme-based antibacterials efficiently kill Gram-positive bacteria upon contact by specific cell wall hydrolysis. However, a major hurdle in their exploitation as antibacterials against Gram-negative pathogens is the impermeable lipopolysaccharide layer surrounding their cell wall. Therefore, we developed and optimized an approach to engineer these enzymes as outer membrane-penetrating endolysins (Artilysins), rendering them highly bactericidal against Gram-negative pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. Artilysins combining a polycationic nonapeptide and a modular endolysin are able to kill these (multidrug-resistant) strains in vitro with a 4 to 5 log reduction within 30 min. We show that the activity of Artilysins can be further enhanced by the presence of a linker of increasing length between the peptide and endolysin or by a combination of both polycationic and hydrophobic/amphipathic peptides. Time-lapse microscopy confirmed the mode of action of polycationic Artilysins, showing that they pass the outer membrane to degrade the peptidoglycan with subsequent cell lysis. Artilysins are effective in vitro (human keratinocytes) and in vivo (Caenorhabditis elegans). Importance: Bacterial resistance to most commonly used antibiotics is a major challenge of the 21st century. Infections that cannot be treated by first-line antibiotics lead to increasing morbidity and mortality, while millions of dollars are spent each year by health care systems in trying to control antibiotic-resistant bacteria and to prevent cross-transmission of resistance. Endolysins--enzymes derived from bacterial viruses--represent a completely novel, promising class of antibacterials based on cell wall hydrolysis. Specifically, they are active against Gram-positive species, which lack a protective outer membrane and which have a low probability of resistance development. We modified endolysins by protein engineering to create Artilysins that are able to pass the outer membrane and become active against Pseudomonas aeruginosa and Acinetobacter baumannii, two of the most hazardous drug-resistant Gram-negative pathogens.

Project description:BackgroundEmerging worldwide in the past decade, there has been a significant increase in multidrug-resistant bacteria from serious nosocomial infections, especially carbapenemase-producing Gram-negative bacilli that have emerged worldwide. The objective of this study is to investigate carbapenem resistance in Gram-negative bacilli bacteria using phenotypic detection, antimicrobial resistance profiles and genotypic characterisation methods.Methods200 Gram-negative bacilli isolates were collected from different clinical specimens. All clinical samples were exposed to isolation and identification of significant pathogens applying bacteriological examination and an automated Vitek-2 system. The isolates were subjected to susceptibility tests by the Vitek-2 automated system and those isolates that were resistant to beta-lactam drugs, including carbapenems, third-generation cephalosporines or cefoxitin, were selected for phenotyping using Carba plus disc system assay for detection of carbapenemase-producing isolates. These isolates were further confirmed by molecular detection. PCR was used for the detection carbapenem-resistant genes (OXA-48, IMP, NDM, VIM, and KPC).Results110 (55%) of 200 Gram-negative bacilli were identified as beta-lactam-resistant isolates. The frequency of carbapenem-resistant isolates was calculated to be 30.9% (n = 34/110). A collection totalling 65/110 (59%) isolates were identified as carbapenemase producers by phenotypic method. Moreover, among the 65 carbapenemase-producing Gram-negative isolates with a positive phenotype-based result, 30 (46%), 20 (30%) and 18 (27%) isolates were positive for OXA-48, KPC and MBL enzymes, respectively, as well as the production of 27% of AmpC with porin loss. Tigecycline was the most effective antibiotic that affected 70% of MDR isolates, but high rates of resistance were detected to other tested antimicrobials. Of interest, a high incidence of MDR, XDR and PDR profiles were observed among all carbapenemase-producing isolates. 36% (24/65) of the tested isolates were MDR to 3 to 5 antimicrobial classes. 29% (17/65) of the recovered isolates were XDR to 6 to 7 antimicrobial classes. Alarmingly, 24% (16/65) of isolates displayed PDR to all the tested 8 antimicrobial classes. Genotype assay, including 53 phenotypically confirmed carbapenemase-producing isolates of Gram-negative bacilli, found 51(96%) isolates were harbouring one or more genes. The most common carbapenemase gene was bla NDM 83% (44/53) followed by bla OXA-48 75% (40/53), bla VIM 49% (26/53) and bla IMP 43% (23/53), while the gene bla KPC was least frequent 7% (4/53). 92% (46/51) of isolates were involved in the production of more than one carbapenemase gene.ConclusionThis study demonstrated the emergence of carbapenemase-producing Gram-negative pathogens implicated in healthcare-related infections. Accurate identification of carbapenem-resistant bacterial pathogens is essential for patient treatment, as well as the development of appropriate contamination control measures to limit the rapid spread of pathogens. Tigecycline exhibited potent antimicrobial activity against MDR, XDR and PDR-producing strains that establish a threatening alert which indicates the complex therapy of infections caused by these pathogens.

Project description:Background:Treatment and prevention of wound infection continues to be a challenging issue in clinical settings of Nepal especially in the context of globally growing problem of antimicrobial resistance. Study on opportunistic pathogens and sensitivity to commonly prescribed local antimicrobial agents are cardinal to reduce the disease burden of wound infections. The aim of this study was to determine the prevalence and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus (MRSA) and extended spectrum ?-lactamase (ESBL) producing bacteria from wound infections of patients at a tertiary care hospital in Nepal. Methods:Pus specimens were processed using standard microbiological procedures. Antimicrobial susceptibility test was performed following the modified Kirby Bauer disc diffusion technique. Clinical information of patients was obtained from preformed questionnaire and hospital record. Results:One hundred eighty two pus specimens from wounds of different body parts: leg, hand, backside, abdominal part, foot, breast and chest, head and neck region were collected and analyzed; 113 bacterial isolates were isolated showing the overall bacterial growth rate of 62%, where the highest rate was among patients of ?10 years age group (82.1%). A higher rate (68.5%) of bacterial isolates were from inpatients (p?<?0.05). Among 116 bacterial isolates, Staphylococcus aureus was the most predominant bacteria (56.9%) followed by Escherichia coli (8.6%), coagulase negative staphylococci (7.8%), Acinetobacter spp. (5.2%), Klebsiella pneumoniae (5.2%), Pseudomonas aeruginosa (4.3%), Enterococcus spp. (4.3%), Citrobacter freundii (2.6%), Proteus vulgaris (1.6%) and P. mirabilis (0.9%). Both Gram positive (73.3%) and negative (78.8%) isolates showed high frequency of sensitive to gentamycin. Conclusion:Among S. aureus isolates, 60.6% were MRSA strains, whereas 40% of K. pneumoniae and 33.3% of C. freundii were ESBL producing bacteria followed by E. coli (25%). It is thus paramount to address the burden of silently and speedily increasing infections caused by drug resistant strains of MRSA and ESBL in Nepal.

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Potential Tamoxifen Repurposing to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli.

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