scholarly journals Identification, Characterization, and Formulation of a Novel Carbapenemase Intended to Prevent Antibiotic-Mediated Gut Dysbiosis

2019 ◽  
Vol 7 (1) ◽  
pp. 22 ◽  
Author(s):  
Sheila Connelly ◽  
Todd Parsley ◽  
Hui Ge ◽  
Michael Kaleko
Keyword(s):  
Gut Microbiome ◽  
Opportunistic Infections ◽  
New Delhi ◽  
Beta Lactamase ◽  
Gi Tract ◽  
Beta Lactam ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Beta Lactam Antibiotics ◽  
Antibiotic Degradation

Antibiotics can damage the gut microbiome leading to opportunistic infections and the emergence of antibiotic resistance. Microbiome protection via antibiotic inactivation in the gastrointestinal (GI) tract represents a strategy to limit antibiotic exposure of the colonic microbiota. Proof of concept for this approach was achieved with an orally-administered beta-lactamase enzyme, SYN-004 (ribaxamase), that was demonstrated to degrade ceftriaxone excreted into the GI tract and protect the gut microbiome from antibiotic-mediated dysbiosis. Ribaxamase efficiently degrades penicillin and cephalosporin beta-lactam antibiotics, but is not active against carbapenems. To expand this microbiome protection strategy to include all classes of beta-lactams, three distinct carbapenemases were evaluated for manufacturability, antibiotic degradation spectrum, and stability in human intestinal fluid. E. coli production strains were generated for P2A, a novel metallo-enzyme isolated from B. cereus, New Delhi metallo-beta-lactamase (NDM), and Klebsiella pneumoniae carbapenemase (KPC). While all three enzymes effectively inactivated a broad range of antibiotics, including penicillins, most cephalosporins, and carbapenems in vitro, only P2A retained biological activity when incubated with human chyme. As functional stability in the intestinal tract is a key requirement for an orally-delivered enzyme, P2A was chosen as a potential clinical candidate. An enteric formulation of P2A was developed, called SYN-006, that was inert under high acid conditions, with enzyme dissolution occurring at pH > 5.5. SYN-006 has the potential to expand microbiome protection via antibiotic inactivation to include all classes of beta-lactam antibiotics.

scholarly journals Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage

2019 ◽  
Vol 7 (5) ◽  
pp. 150 ◽  
Author(s):  
Sheila Connelly ◽  
Brian Fanelli ◽  
Nur A. Hasan ◽  
Rita R. Colwell ◽  
Michael Kaleko
Keyword(s):  
Antibiotic Resistance ◽  
Small Intestine ◽  
Resistance Genes ◽  
Gut Microbiome ◽  
Antibiotic Resistance Genes ◽  
Oral Antibiotic ◽  
Beta Lactamase ◽  
Gi Tract ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics

Antibiotics damage the gut microbiome, which can result in overgrowth of pathogenic microorganisms and emergence of antibiotic resistance. Inactivation of antibiotics in the small intestine represents a novel strategy to protect the colonic microbiota. SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract. The enteric coating of ribaxamase protects the enzyme from stomach acid and mediates pH-dependent release in the upper small intestine, the site of antibiotic biliary excretion. Clinical benefit was established in animal and human studies in which ribaxamase was shown to degrade ceftriaxone in the GI tract, thereby preserving the gut microbiome, significantly reducing Clostridioides difficile disease, and attenuating antibiotic resistance. To expand ribaxamase utility to oral beta-lactams, delayed release formulations of ribaxamase, SYN-007, were engineered to allow enzyme release in the lower small intestine, distal to the site of oral antibiotic absorption. Based on in vitro dissolution profiles, three SYN-007 formulations were selected for evaluation in a canine model of antibiotic-mediated gut dysbiosis. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were measured after the first and last antibiotic doses and gut microbiomes were evaluated using whole genome shotgun sequence metagenomics analyses of fecal DNA prior to and after antibiotic treatment. Serum amoxicillin levels did not significantly differ +/- SYN-007 after the first dose for all SYN-007 formulations, while only one SYN-007 formulation did not significantly reduce systemic antibiotic concentrations after the last dose. Gut microbiomes of animals receiving amoxicillin alone displayed significant loss of diversity and emergence of antibiotic resistance genes. In contrast, for animals receiving amoxicillin + SYN-007, microbiome diversities were not altered significantly and the presence of antibiotic resistance genes was reduced. These data demonstrate that SYN-007 diminishes amoxicillin-mediated microbiome disruption and mitigates emergence and propagation of antibiotic resistance genes without interfering with antibiotic systemic absorption. Thus, SYN-007 has the potential to protect the gut microbiome by inactivation of beta-lactam antibiotics when administered by both oral and parenteral routes and to reduce emergence of antibiotic-resistant pathogens.

scholarly journals In Vitro Susceptibilities of Capnocytophaga Isolates to beta -Lactam Antibiotics and beta -Lactamase Inhibitors

2000 ◽  
Vol 44 (11) ◽  
pp. 3186-3188 ◽  
Author(s):  
A. Jolivet-Gougeon ◽  
A. Buffet ◽  
C. Dupuy ◽  
J.-L. Sixou ◽  
M. Bonnaure-Mallet ◽  
...  
Keyword(s):  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics

scholarly journals Detection of New Delhi Metallo b Lactamase gene in Uropathogenic E. coli

2019 ◽  
Vol 36 (1) ◽  
pp. 29-33
Author(s):  
Sunjukta Ahsan ◽  
Anindita Bhowmik ◽  
Sharmistha Goswami ◽  
Nasir Uddin
Keyword(s):  
Treatment Options ◽  
Pcr Amplification ◽  
Health Concern ◽  
New Delhi ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
E Coli ◽  
Beta Lactam Antibiotics ◽  
Amoxicillin Clavulanate ◽  
Lactamase Gene

The rapid dissemination of antibiotic resistant E. coli is now a worldwide problem. In this study, a total of twenty E. coli obtained from stool were selected to determine resistance to beta lactam antibiotics. Beta–Lactamase are enzymes produced by bacteria that provide multi resistance to beta lactam antibiotics such as penicillin, cephalosporin, cephamycin and carbapenems. Of these isolates (n = 20), 35% were found resistant to Amoxicillin Clavulanate, 5% to Imipenem, 50% to Ceftriaxone and 75% to Ampicillin. PCR amplification confirmed the presence of the New Delhi beta-lactamase gene (blaNDM) in one isolate (5%, n=20). Plasmids of variable sizes were found in all the isolates. Beta lactam antibiotics are now commonly used for the treatment of disease. Resistance of 50% of the isolates to Ceftriaxone is alarming as this indicates that an alternative drug may soon need to replace this antibiotic for successful treatment. The finding of this study is also of public health concern as plasmids were found in most isolates and these mobile genetic elements can be transferred among clinical bacteria, thereby disseminating antibiotic resistance further limiting treatment options. Bangladesh J Microbiol, Volume 36 Number 1 June 2019, pp 29-33

scholarly journals Beta‐lactamase‐producing Escherichia coli in Bangladesh: Their phenotypic and molecular characteristics

2019 ◽  
Vol 28 (1) ◽  
pp. 71-81
Author(s):  
Sunjukta Ahsan ◽  
Riajul Islam
Keyword(s):  
Health Concern ◽  
Resistance Pattern ◽  
Molecular Characteristics ◽  
New Delhi ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Class 1 Integron ◽  
E Coli ◽  
Beta Lactam Antibiotics ◽  
Class 1

The emergence and rapid dissemination of beta-lactamase-producing E. coli is now a worldwide problem. A total of 45 E. coli obtained from clinical specimens from a medical service centre in Dhaka were selected for this study. Test E. coli exhibited variable resistance to 3rd (71.7 - 97.8%, n = 48) and 4th (78%, n = 48) generation beta-lactam antibiotics, with 72% sensitivity to Carbapenem. Analysis of co-resistance indicated that 33.3% of E. coli (n = 48) were co-resistant to beta-lactams and ciprofloxacin. ESBL producers were predominant comprising of 84.7% E. coli. Among them, 22.7% contained blaTEM, 24.2% contained blaCTX-M, 4.3% contained blaSHV and 9.1% contained blaOXA-1 genes. A total of 25.75% isolates were metallo beta-lactamase producers. Of these, 1.5% of E. coli strains contained New Delhi metallo beta-lactamase gene and 6% contained AmpC gene. Multiple beta-lactamase genes were detected in some test isolates; 6.7% isolates contained 4, 20% contained 3 and 73.3% contained 2 beta lactamase genes. Fifty per cent of the E. coli contained plasmids of variable sizes. In addition, a total of 39% of the E. coli contained Class 1 integron. The increasing trend in beta-lactam resistance is of public health concern as it limits treatment regime and indicates to the need of continuous monitoring of resistance pattern. Dhaka Univ. J. Biol. Sci. 28(1): 71-81, 2019 (January)

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