The Gut Microbiota of Healthy Infants in the Community is a Reservoir for ESBL and Carbapenemase Producing Bacteria.

Abstract Background The recent rapid rise of Extended-spectrum Β Lactamase producing Gram-negative bacteria (ESBL-GNB) has seriously threatened the treatment of common infectious diseases. Neonates have an immature immune system and a delay in appropriate treatment due to ESBL-GNB sepsis can be fatal. This problem of delayed therapy is magnified in the developing world where 99% of the deaths from community acquired neonatal sepsis occur. Additionally ESBL E. coli such as the strain ST131 are known to be persistent gut and vaginal colonizers. In animal models, these strains out-compete colonization with drug-sensitive, commensal E. coli. Gut colonization with ESBL-GNB in infants may therefore have a profound impact on their microbiome and increase their risk of sepsis. Pakistan is a lower middle income country with high antibiotic use per capita and a sharp increase in ESBL-GNB infections. Recent data show that >50% of E. coli isolates from reproductive-aged women of Pakistan are resistant to more than one class of antibiotics. We aimed to determine the rates of gut colonization with ESBL-GNB among healthy infants in a community setting. Methods Stool samples were collected from 100 healthy infants living in a Pakistani suburban community between the ages of 5 and 7 months. Samples were plated on MacConkey agar to select for Gram-negative bacteria. Isolates were screened for resistance against several antimicrobial classes. Molecular testing of the stool samples was done using primers targeting conserved regions of ESBL and carbapenemase genes. Results Forty-eight percent of the infants were positive for ESBL producing Gram-negative bacteria, the majority of which were E. coli, and 7.5% were positive for carbapenemase producers, all of which belonged to Klebsiella spp. Molecular testing showed that 85% of the infant stools were positive for TEM β-lactamase gene, 68% for the CTX-M β-lactamase gene and 33% for the KPC carbapenemase gene. Conclusion The widespread colonization of infants in a developing country with ESBL-GNB is highly concerning. Further, our studies have revealed that the resistome of otherwise healthy infants may be a major reservoir of antibiotic genes in the community. Gut microbiome analysis of the potential impact of colonization with antibiotic-resistant bacteria is on-going. Disclosures All authors: No reported disclosures.

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Investigation of urban birds as source of β-lactamase-producing Gram-negative bacteria in Marseille city, France

Acta Veterinaria Scandinavica ◽

10.1186/s13028-019-0486-9 ◽

2019 ◽

Vol 61 (1) ◽

Cited By ~ 4

Author(s):

Edgarthe Priscilla Ngaiganam ◽

Isabelle Pagnier ◽

Wafaa Chaalal ◽

Thongpan Leangapichart ◽

Selma Chabou ◽

...

Keyword(s):

Resistance Genes ◽

Antibiotic Resistance Genes ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Urban Birds ◽

Multidrug Resistant Bacteria ◽

Gram Negative ◽

E Coli ◽

Stool Samples

Abstract Background We investigate here the presence of multidrug-resistant bacteria isolated from stool samples of yellow-legged gulls and chickens (n = 136) in urban parks and beaches of Marseille, France. Bacterial isolation was performed on selective media, including MacConkey agar with ceftriaxone and LBJMR medium. Antibiotic resistance genes, including extended-spectrum β-lactamases (ESBL) (i.e. blaCTX-M, blaTEM and blaSHV), carbapenemases (blaKPC, blaVIM, blaNDM, blaOXA-23, blaOXA-24, blaOXA-48 and blaOXA-58) and colistin resistance genes (mcr-1 to mcr-5) were screened by real-time PCR and standard PCR and sequenced when found. Results Of the 136 stools samples collected, seven ESBL-producing Gram-negative bacteria (BGN) and 12 colistin-resistant Enterobacteriaceae were isolated. Among them, five ESBL-producing Escherichia coli and eight colistin-resistant Hafnia alvei strains were identified. Four blaTEM-1 genes were detected in yellow-legged gulls and chickens. Three CTX-M-15 genes were detected in yellow-legged gulls and pigeons, and one CTX-M-1 in a yellow-legged gull. No mcr-1 to mcr-5 gene were detected in colistin-resistant isolates. Genotyping of E. coli strains revealed four different sequence types already described in humans and animals and one new sequence type. Conclusions Urban birds, which are believed to have no contact with antibiotics appear as potential source of ESBL genes. Our findings highlight the important role of urban birds in the proliferation of multidrug-resistant bacteria and also the possible zoonotic transmission of such bacteria from wild birds to humans.

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AmpN-AmpG Operon Is Essential for Expression of L1 and L2 β-Lactamases in Stenotrophomonas maltophilia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01283-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2583-2589 ◽

Cited By ~ 22

Author(s):

Yi-Wei Huang ◽

Cheng-Wen Lin ◽

Rouh-Mei Hu ◽

Yu-Tzu Lin ◽

Tung-Ching Chung ◽

...

Keyword(s):

Stenotrophomonas Maltophilia ◽

Gene Dosage ◽

Gram Negative Bacteria ◽

Beta Lactamase ◽

Gene Dosage Effect ◽

Gram Negative ◽

E Coli ◽

Murein Sacculus ◽

Lactamase Gene ◽

L1 And L2

ABSTRACT AmpG is an inner membrane permease which transports products of murein sacculus degradation from the periplasm into the cytosol in Gram-negative bacteria. This process is linked to induction of the chromosomal ampC beta-lactamase gene in some members of the Enterobacteriaceae and in Pseudomonas aeruginosa. In this study, the ampG homologue of Stenotrophomonas maltophilia KJ was analyzed. The ampG homologue and its upstream ampN gene form an operon and are cotranscribed under the control of the promoter P ampN. Expression from P ampN was found to be independent of β-lactam exposure and ampN and ampG products. A ΔampN allele exerted a polar effect on the expression of ampG and resulted in a phenotype of null β-lactamase inducibility. Complementation assays elucidated that an intact ampN-ampG operon is essential for β-lactamase induction. Consistent with ampG of Escherichia coli, the ampN-ampG operon of S. maltophilia did not exhibit a gene dosage effect on β-lactamase expression. The AmpG permease of E. coli could complement the β-lactamase inducibility of ampN or ampG mutants of S. maltophilia, indicating that both species have the same precursor of activator ligand(s) for β-lactamase induction.

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Innolysins: A novel approach to engineer endolysins to kill Gram-negative bacteria

10.1101/408948 ◽

2018 ◽

Cited By ~ 4

Author(s):

Athina Zampara ◽

Martine C. Holst Sørensen ◽

Dennis Grimon ◽

Fabio Antenucci ◽

Yves Briers ◽

...

Keyword(s):

Outer Membrane ◽

Receptor Binding ◽

Binding Proteins ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Proof Of Concept ◽

Gram Negative ◽

E Coli ◽

Phage Receptor ◽

Alternative Antimicrobials

ABSTRACTBacteriophage-encoded endolysins degrading the essential peptidoglycan of bacteria are promising alternative antimicrobials to handle the global threat of antibiotic resistant bacteria. However, endolysins have limited use against Gram-negative bacteria, since their outer membrane prevents access to the peptidoglycan. Here we present Innolysins, a novel concept for engineering endolysins that allows the enzymes to pass through the outer membrane, hydrolyse the peptidoglycan and kill the target bacterium. Innolysins combine the enzymatic activity of endolysins with the binding capacity of phage receptor binding proteins (RBPs). As our proof of concept, we used phage T5 endolysin and receptor binding protein Pb5, which binds irreversibly to the phage receptor FhuA involved in ferrichrome transport inEscherichia coli. In total, we constructed twelve Innolysins fusing endolysin with Pb5 or the binding domain of Pb5 with or without flexible linkers in between. While the majority of the Innolysins maintained their muralytic activity, Innolysin#6 also showed bactericidal activity againstE. colireducing the number of bacteria by 1 log, thus overcoming the outer membrane barrier. Using anE. coli fhuAdeletion mutant, we demonstrated that FhuA is required for bactericidal activity, supporting that the specific binding of Pb5 to its receptor onE. coliis needed for the endolysin to access the peptidoglycan. Accordingly, Innolysin#6 was able to kill other bacterial species that carry conserved FhuA homologs such asShigella sonneiandPseudomonas aeruginosa. In summary, the Innolysin approach expands recent protein engineering strategies allowing customization of endolysins by exploiting phage RBPs to specifically target Gram-negative bacteria.IMPORTANCEThe extensive use of antibiotics has led to the emergence of antimicrobial resistant bacteria responsible for infections causing more than 50,000 deaths per year across Europe and the US. In response, the World Health Organization has stressed an urgent need to discover new antimicrobials to control in particular Gram-negative bacterial pathogens, due to their extensive multi-drug resistance. However, the outer membrane of Gram-negative bacteria limits the access of many antibacterial agents to their targets. Here, we developed a new approach, Innolysins that enable endolysins to overcome the outer membrane by exploiting the binding specificity of phage receptor binding proteins. As proof of concept, we constructed Innolysins againstE. coliusing the endolysin and the receptor binding protein of phage T5. Given the rich diversity of phage receptor binding proteins and their different binding specificities, our proof of concept paves the route for creating an arsenal of pathogen specific alternative antimicrobials.

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Dissemination of Carbapenem-resistance and Plasmids-encoding Carbapenemases in Gram-negative Bacteria Isolated from India

10.1101/2020.05.18.102434 ◽

2020 ◽

Author(s):

Prasanth Manohar ◽

Sebastian Leptihn ◽

Bruno S. Lopes ◽

Nachimuthu Ramesh

Keyword(s):

Tamil Nadu ◽

Treatment Options ◽

Public Health Problem ◽

Carbapenem Resistance ◽

Gram Negative Bacteria ◽

Gram Negative ◽

E Coli ◽

Diagnostic Center ◽

Lactamase Gene

AbstractCarbapenem resistance in Gram-negative bacteria is an ongoing public-health problem of global dimensions leaving very few treatment options for severely infected patients. This study focuses on the dissemination of plasmid-borne carbapenemase genes in Gram-negative bacteria in Tamil Nadu, India. A total of 151 non-repetitive isolates belonging to 11 genera were collected from a diagnostic center in Tamil Nadu. E. coli (n=57) isolates were classified as, Enteropathogenic (n=12), Enteroaggregative (n=9), Enterohemorrhagic (n=8), Enterotoxigenic (n=3), Enteroinvasive (n=1) and unclassified E. coli (n=24). Of the 45 Klebsiella species, 14 were K1 whereas 11 were K2 serotype and in 20 Klebsiella serotype could not be determined. Other isolates (n=49) consisted of P. aeruginosa, S. typhi, E. cloacae, A. baumannii, S. marcescens, A. xylosoxidans, P. mirabilis and E. meningoseptica. Of the 151 isolates, 71% (n=107) and 68% (n=103) were found to be resistant to meropenem and imipenem respectively. The most prevalent beta-lactamase gene was blaNDM-1 (21%, 12/57) followed by blaOXA-181 (16%, 9/57), blaGES-9 (n=8), blaOXA-23 (n=7), blaIMP-1 (n=3), blaGES-1 (n=11) and blaOXA-51 (n=9). The unusual presence of blaOXA-23 was seen in E. coli (n=4), and blaOXA-23 and blaOXA-51 (IncA/C) in K. pneumoniae (n=3). Plasmid incompatibility (inc/rep) typing results showed that the plasmids carrying resistance genes (n=11) belonged to IncX, IncA/C, IncFIA-FIB and IncFIIA groups. E. coli and K. pneumoniae were able to transfer plasmid-borne carbapenemase via conjugation. This study highlights the prevalence of carbapenem resistance and the acquisition of plasmid-borne carbapenemase genes in Gram-negative bacteria highlighting the role of plasmid transfer in disseminating resistance.

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Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R againstEscherichia coli

PeerJ ◽

10.7717/peerj.3168 ◽

2017 ◽

Vol 5 ◽

pp. e3168 ◽

Cited By ~ 14

Author(s):

Diana Machado ◽

Laura Fernandes ◽

Sofia S. Costa ◽

Rolando Cannalire ◽

Giuseppe Manfroni ◽

...

Keyword(s):

Mode Of Action ◽

Bacterial Infections ◽

Efflux Pump ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Synergistic Activity ◽

Dependent Manner ◽

Gram Negative ◽

E Coli ◽

Efflux Pump Inhibitors

Efflux pump inhibitors are of great interest since their use as adjuvants of bacterial chemotherapy can increase the intracellular concentrations of the antibiotics and assist in the battle against the rising of antibiotic-resistant bacteria. In this work, we have described the mode of action of the 2-phenylquinoline efflux inhibitor (4-(2-(piperazin-1-yl)ethoxy)-2-(4-propoxyphenyl) quinolone – PQQ4R), againstEscherichia coli,by studding its efflux inhibitory ability, its synergistic activity in combination with antibiotics, and compared its effects with the inhibitors phenyl-arginine-β-naphthylamide (PAβN) and chlorpromazine (CPZ). The results showed that PQQ4R acts synergistically, in a concentration dependent manner, with antibiotics known to be subject to efflux inE. colireducing their MIC in correlation with the inhibition of their efflux. Real-time fluorometry assays demonstrated that PQQ4R at sub-inhibitory concentrations promote the intracellular accumulation of ethidium bromide inhibiting its efflux similarly to PAβN or CPZ, well-known and described efflux pump inhibitors for Gram-negative bacteria and whose clinical usage is limited by their levels of toxicity at clinical and bacteriological effective concentrations. The time-kill studies showed that PQQ4R, at bactericidal concentrations, has a rapid antimicrobial activity associated with a fast decrease of the intracellular ATP levels. The results also indicated that the mode of action of PQQ4R involves the destabilization of theE. coliinner membrane potential and ATP production impairment, ultimately leading to efflux pump inhibition by interference with the energy required by the efflux systems. At bactericidal concentrations, membrane permeabilization increases and finally ATP is totally depleted leading to cell death. Since drug resistance mediated by the activity of efflux pumps depends largely on the proton motive force (PMF), dissipaters of PMF such as PQQ4R, can be regarded as future adjuvants of conventional therapy againstE. coliand other Gram-negative bacteria, especially their multidrug resistant forms. Their major limitation is the high toxicity for human cells at the concentrations needed to be effective against bacteria. Their future molecular optimization to improve the efflux inhibitory properties and reduce relative toxicity will optimize their potential for clinical usage against multi-drug resistant bacterial infections due to efflux.

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Association between the rate of fluoroquinolones-resistant Gram-negative bacteria and antibiotic consumption from China based on 145 tertiary hospitals data in 2014

10.21203/rs.2.17294/v1 ◽

2019 ◽

Author(s):

Ping Yang ◽

Yunbo Chen ◽

Saiping Jiang ◽

Ping Shen ◽

Xiaoyang Lu ◽

...

Keyword(s):

Antibiotic Consumption ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Gram Negative ◽

E Coli ◽

Annual Consumption ◽

Tertiary Hospitals ◽

The Relationship ◽

Third Generation Cephalosporins ◽

Consumption Intensity

Abstract This study aimed to investigate the relationship between the rate of fluoroquinolones-resistant (FQR) gram-negative bacteria and antibiotic consumption intensity in 145 tertiary hospitals from China in 2014.Methods A retrospective study using national surveillance data from 2014 was conducted. Data on the annual consumption of each antibiotic, and the rate of FQR gram-negative bacteria, were collected from each participating hospital, and the correlation between antibiotic consumption and FQR rate was simultaneously investigated.Results The overall antibiotic consumption intensity among the hospitals varied between 23.93 and 115.39 defined daily dosages (DDDs) per 100 patient-days (median, 46.30 DDDs per 100 patient-days). Cephalosporins were the most commonly prescribed antibiotics, followed by fluoroquinolones, penicillins, and carbapenems, and the rate of FQR gram-negative bacteria from each hospital varied. The correlation analysis showed significantly relationship between the percentage of FQR E. coli and the consumption of FQs consumption (r=0.308, p<0.01) and levofloxacin (r=0.252, p<0.01). For FQR K. pneumoniae, not only FQs (r=0.291, p<0.01) and levofloxacin (r=0.260, p<0.01) use but also carbapenems (r=0.242, p<0.01) and overall antibiotics (r=0.247, p<0.01) use showed significant correlation. A strong correlation was observed between the resistant proportion of FQR P. aeruginosa and the consumption of all antibiotics (r=0.260, p<0.01), FQs (r=0.319, p<0.01) and levofloxacin (r=0.377, p<0.01). The percentage of levofloxacin-resistant A. baumannii was significantly correlated with the consumption of all antibiotics (r=0.282, p<0.01), third-generation cephalosporins excluding combinations with beta-lactamase inhibitors (r=0.246, p<0.01), FQs (r=0.254, p<0.01) and levofloxacin (r=0.336, p<0.01). However, the correlation of the ciprofloxacin-resistant A. baumannii and the antibiotics consumption was not found.Conclusions A significant relationship was demonstrated between the antibiotic consumption and the rates of FQR gram-negative bacteria. As unreasonable antibiotics usage remains crucial in the proceeding of resistant bacteria selection, our study could greatly promote the avoidance of unnecessary antibiotic usage.

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LpxT-Dependent Phosphorylation of Lipid A in Escherichia coli Increases Resistance to Deoxycholate and Enhances Gut Colonization

Frontiers in Microbiology ◽

10.3389/fmicb.2021.676596 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xudong Tian ◽

Guillaume Manat ◽

Elise Gasiorowski ◽

Rodolphe Auger ◽

Samia Hicham ◽

...

Keyword(s):

Escherichia Coli ◽

Cell Surface ◽

Lipid A ◽

Negative Charge ◽

Polymyxin B ◽

Gram Negative Bacteria ◽

Bacterial Cells ◽

Gram Negative ◽

E Coli ◽

Gut Colonization

The cell surface of Gram-negative bacteria usually exhibits a net negative charge mostly conferred by lipopolysaccharides (LPS). This property sensitizes bacterial cells to cationic antimicrobial peptides, such as polymyxin B, by favoring their binding to the cell surface. Gram-negative bacteria can modify their surface to counteract these compounds such as the decoration of their LPS by positively charged groups. For example, in Escherichia coli and Salmonella, EptA and ArnT add amine-containing groups to the lipid A moiety. In contrast, LpxT enhances the net negative charge by catalyzing the synthesis of tri-phosphorylated lipid A, whose function is yet unknown. Here, we report that E. coli has the intrinsic ability to resist polymyxin B upon the simultaneous activation of the two component regulatory systems PhoPQ and PmrAB by intricate environmental cues. Among many LPS modifications, only EptA- and ArnT-dependent decorations were required for polymyxin B resistance. Conversely, the acquisition of polymyxin B resistance compromised the innate resistance of E. coli to deoxycholate, a major component of bile. The inhibition of LpxT by PmrR, under PmrAB-inducing conditions, specifically accounted for the acquired susceptibility to deoxycholate. We also report that the kinetics of intestinal colonization by the E. coli lpxT mutant was impaired as compared to wild-type in a mouse model of infection and that lpxT was upregulated at the temperature of the host. Together, these findings highlight an important function of LpxT and suggest that a tight equilibrium between EptA- and LpxT-dependent decorations, which occur at the same position of lipid A, is critical for the life style of E. coli.

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Inhibition of Multidrug-Resistant Gram-Positive and Gram-Negative Bacteria by a Photoactivated Porphyrin

Polish Journal of Microbiology ◽

10.5604/01.3001.0010.7092 ◽

2017 ◽

Vol 66 (4) ◽

pp. 533-536 ◽

Cited By ~ 2

Author(s):

Moreno Bondi ◽

Anna Mazzini ◽

Simona de Niederhäusern ◽

Ramona Iseppi ◽

Patrizia Messi

Keyword(s):

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Multidrug Resistant Bacteria ◽

Gram Positive ◽

Gram Negative ◽

E Coli ◽

In Vitro Antibacterial Activity

The authors studied the in vitro antibacterial activity of the photo-activated porphyrin meso-tri(N-methyl-pyridyl), mono(N-tetradecyl-pyridyl)porphine (C14) against four multidrug-resistant bacteria: Staphylococcus aureus, Enterococcus faecalis (Gram-positive), Escherichia coli, Pseudomonas aeruginosa (Gram-negative). Using 10 μg/ml of porphyrin and 60 sec irradiation we observed the remarkable susceptibility of S. aureus and E. faecalis to treatment while, under the same conditions, E. coli and P. aeruginosa showed very low susceptibility. In a later stage, suspensions of Gram-negative bacteria were processed with EDTA before photo-activation, obtaining a significant decrease in viable counts. In view of the results, if the combination of low porphyrin concentrations and short irradiation times will be effective in vivo also, this approach could be a possible alternative to antibiotics, in particular against localized infections due to multidrug-resistant microorganisms.

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Fluorescence High-Throughput Screening for Inhibitors of TonB Action

Journal of Bacteriology ◽

10.1128/jb.00889-16 ◽

2017 ◽

Vol 199 (10) ◽

Cited By ~ 11

Author(s):

Brittany L. Nairn ◽

Olivia S. Eliasson ◽

Dallas R. Hyder ◽

Noah J. Long ◽

Aritri Majumdar ◽

...

Keyword(s):

Escherichia Coli ◽

Acinetobacter Baumannii ◽

High Throughput ◽

High Throughput Screening ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Compound Libraries

ABSTRACT Gram-negative bacteria acquire ferric siderophores through TonB-dependent outer membrane transporters (TBDT). By fluorescence spectroscopic hgh-throughput screening (FLHTS), we identified inhibitors of TonB-dependent ferric enterobactin (FeEnt) uptake through Escherichia coli FepA (EcoFepA). Among 165 inhibitors found in a primary screen of 17,441 compounds, we evaluated 20 in secondary tests: TonB-dependent ferric siderophore uptake and colicin killing and proton motive force-dependent lactose transport. Six of 20 primary hits inhibited TonB-dependent activity in all tests. Comparison of their effects on [59Fe]Ent and [14C]lactose accumulation suggested several as proton ionophores, but two chemicals, ebselen and ST0082990, are likely not proton ionophores and may inhibit TonB-ExbBD. The facility of FLHTS against E. coli led us to adapt it to Acinetobacter baumannii. We identified its FepA ortholog (AbaFepA), deleted and cloned its structural gene, genetically engineered 8 Cys substitutions in its surface loops, labeled them with fluorescein, and made fluorescence spectroscopic observations of FeEnt uptake in A. baumannii. Several Cys substitutions in AbaFepA (S279C, T562C, and S665C) were readily fluoresceinated and then suitable as sensors of FeEnt transport. As in E. coli, the test monitored TonB-dependent FeEnt uptake by AbaFepA. In microtiter format with A. baumannii, FLHTS produced Z′ factors 0.6 to 0.8. These data validated the FLHTS strategy against even distantly related Gram-negative bacterial pathogens. Overall, it discovered agents that block TonB-dependent transport and showed the potential to find compounds that act against Gram-negative CRE (carbapenem-resistant Enterobacteriaceae)/ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Our results suggest that hundreds of such chemicals may exist in larger compound libraries. IMPORTANCE Antibiotic resistance in Gram-negative bacteria has spurred efforts to find novel compounds against new targets. The CRE/ESKAPE pathogens are resistant bacteria that include Acinetobacter baumannii, a common cause of ventilator-associated pneumonia and sepsis. We performed fluorescence high-throughput screening (FLHTS) against Escherichia coli to find inhibitors of TonB-dependent iron transport, tested them against A. baumannii, and then adapted the FLHTS technology to allow direct screening against A. baumannii. This methodology is expandable to other drug-resistant Gram-negative pathogens. Compounds that block TonB action may interfere with iron acquisition from eukaryotic hosts and thereby constitute bacteriostatic antibiotics that prevent microbial colonization of human and animals. The FLHTS method may identify both species-specific and broad-spectrum agents against Gram-negative bacteria.

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Human glucose-dependent insulinotropic polypeptide (GIP) is an antimicrobial adjuvant re-sensitising multidrug-resistant Gram-negative bacteria

Biological Chemistry ◽

10.1515/hsz-2020-0351 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Da’san M. M. Jaradat ◽

Nehaya Al-Karablieh ◽

Basmah H. M. Zaarer ◽

Wenyi Li ◽

Khalil K.Y. Saleh ◽

...

Keyword(s):

Efflux Pump ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Gram Negative ◽

E Coli ◽

Low Concentrations ◽

Bacterial Mutants ◽

Drug Efflux Pumps ◽

Gastrointestinal Peptides

Abstract Increasing antibiotic resistance in Gram-negative bacteria has mandated the development of both novel antibiotics and alternative therapeutic strategies. Evidence of interplay between several gastrointestinal peptides and the gut microbiota led us to investigate potential and broad-spectrum roles for the incretin hormone, human glucose-dependent insulinotropic polypeptide (GIP) against the Enterobacteriaceae bacteria, Escherichia coli and Erwinia amylovora. GIP had a potent disruptive action on drug efflux pumps of the multidrug resistant bacteria E. coli TG1 and E. amylovora 1189 strains. The effect was comparable to bacterial mutants lacking the inner and outer membrane efflux pump factor proteins AcrB and TolC. While GIP was devoid of direct antimicrobial activity, it has a potent membrane depolarizing effect, and at low concentrations, it significantly potentiated the activity of eight antibiotics and bile salt by reducing MICs by 4-8-fold in E. coli TG1 and 4-20-fold in E. amylovora 1189. GIP can thus be regarded as an antimicrobial adjuvant with potential for augmenting the available antibiotic arsenal.

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