A secondary drug resistance mutation of TEM-1 β-lactamase that suppresses misfolding and aggregation

Sideraki, Vera; Huang, Wanzhi; Palzkill, Timothy; Gilbert, Hiram F.

doi:10.1073/pnas.98.1.283

Cited by 79 publications

(63 citation statements)

References 40 publications

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“…However, we did not observe any significant difference in those, at least when comparing susceptibility and resistance to ceftriaxone, ciprofloxacin, and tetracycline (data not shown). Another possibility is that this selective force may be an enhanced stability of the ␤-lactamase enzyme, which the TEM-135-specific amino acid substitution (M182T) is considered to establish (15,21). Usually, this amino acid substitution is found in extended-spectrum TEM-type ␤-lactamase, as the second substitution.…”

Section: Resultsmentioning

confidence: 99%

Molecular Analyses of TEM Genes and Their Corresponding Penicillinase-Producing Neisseria gonorrhoeae Isolates in Bangkok, Thailand

Nakayama

Tribuddharat

Prombhul

et al. 2012

Antimicrob Agents Chemother

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Neisseria gonorrhoeae is a major public health problem globally, especially because the bacterium has developed resistance to most antimicrobials introduced for first-line treatment of gonorrhea. In the present study, 96 N. gonorrhoeae isolates with highlevel resistance to penicillin from 121 clinical isolates in Thailand were examined to investigate changes related to their plasmidmediated penicillin resistance and their molecular epidemiological relationships. A ␤-lactamase (TEM) gene variant, bla , that may be a precursor in the transitional stage of a traditional bla TEM-1 gene into an extended-spectrum ␤-lactamase (ESBL), possibly causing high resistance to all extended-spectrum cephalosporins in N. gonorrhoeae, was identified. Clonal analysis using multilocus sequence typing (MLST) and N. gonorrhoeae multiantigen sequence typing (NG-MAST) revealed the existence of a sexual network among patients from Japan and Thailand. Molecular analysis of the bla TEM-135 gene showed that the emergence of this allele might not be a rare genetic event and that the allele has evolved in different plasmid backgrounds, which results possibly indicate that it is selected due to antimicrobial pressure. The presence of the bla TEM-135 allele in the penicillinaseproducing N. gonorrhoeae population may call for monitoring for the possible emergence of ESBL-producing N. gonorrhoeae in the future. This study identified a bla TEM variant (bla TEM-135 ) that is a possible intermediate precursor for an ESBL, which warrants international awareness. N eisseria gonorrhoeae is the causative agent of gonorrhea, which is the second most prevalent bacterial sexually transmitted infection globally. During recent decades, N. gonorrhoeae has rapidly developed resistance to most classes of antimicrobials used for treatment of gonorrhea (4,6,17,18,20). Penicillinase-producing N. gonorrhoeae (PPNG), with plasmid-mediated high-level resistance to penicillin, was first reported in 1976 (1, 14) and has since been disseminated worldwide (2). The first gonococcal strain with high-level clinical resistance to ceftriaxone, which is the last remaining option for first-line gonorrhea treatment, was recently found in Japan and completely characterized (9, 11). However, the resistance to ceftriaxone was chromosomally mediated, and no extended-spectrum ␤-lactamase (ESBL) has yet been identified in N. gonorrhoeae. If an ESBL did emerge in N. gonorrhoeae and spread internationally, gonorrhea would become an extremely serious public health problem. PPNG strains are rare in Japan, but these strains have remained highly prevalent in several other countries in Asia (19) and worldwide (20). Penicillin is still also used as the first-line drug in, e.g., some Pacific island countries and the northern part of Australia, because of maintained efficacy in the settings and its low cost.Although the ␤-lactamase (TEM) gene of authentic PPNG is the bla TEM-1 allele, a recently isolated PPNG in Thailand possessed the bla TEM-135 allele, which differs from the bla TEM-1 allel...

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Section: Resultsmentioning

confidence: 99%

Molecular Analyses of TEM Genes and Their Corresponding Penicillinase-Producing Neisseria gonorrhoeae Isolates in Bangkok, Thailand

Nakayama

Tribuddharat

Prombhul

et al. 2012

Antimicrob Agents Chemother

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“…The exact mechanism by which M182T functions to decrease aggregation is still to be established. Here the suppressor substitution has been proposed to either inhibit aggregation by changing the conformation of an aggregation-prone intermediate or to alter the folding mechanism in a way to kinetically avoid aggregation (58).…”

Section: Discussionmentioning

confidence: 99%

Alleviation of a Defect in Protein Folding by Increasing the Rate of Subunit Assembly

Aramli

Teschke

2001

Journal of Biological Chemistry

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Understanding the nature of protein grammar is critical because amino acid substitutions in some proteins cause misfolding and aggregation of the mutant protein resulting in a disease state. Amino acid substitutions in phage P22 coat protein, known as tsf (temperature-sensitive folding) mutations, cause folding defects that result in aggregation at high temperatures. We have isolated global su (suppressor) amino acid substitutions that alleviate the tsf phenotype in coat protein (Aramli, L. A., and Teschke, C. M. (1999) J. Biol. Chem. 274, 22217-22224). Unexpectedly, we found that a global su amino acid substitution in tsf coat proteins made aggregation worse and that the tsf phenotype was suppressed by increasing the rate of subunit assembly, thereby decreasing the concentration of aggregation-prone folding intermediates.The primary amino acid sequence of a polypeptide encodes all of the information necessary for folding and assembly pathways, as well as the native three-dimensional structure (2). Substitutions and deletions in the amino acid sequence of a protein can have a significant impact on the ability of a protein to fold or assemble properly. Depending on the protein, such changes in the amino acid sequence can lead to protein misfolding, mislocalization caused by misfolding, or aggregation (3, 4). Amino acid substitutions in p53 lead to a misfolding problem compromising the function of the protein, resulting in cancer (5). Further, there are the diseases that result from mislocalization caused by protein misfolding. For example, in ␣ 1 -antitrypsin deficiency, a single amino acid substitution results in the misfolding of ␣ 1 -antitrypsin, leading to the accumulation of long chain polymers within the hepatocyte. This leads to a reduction of the plasma concentrations of ␣-antitrypsin and predisposes individuals to emphysema and liver disease (6). Therefore, understanding the nature of protein grammar is of paramount interest.Although the process of protein folding is still not completely understood, it is known that larger proteins often have identifiable folding intermediates. These folding intermediates may interact inappropriately before reaching the native state. In fact, protein misfolding is a common problem faced by biotechnology companies that harvest proteins of commercial interest using recombinant DNA technologies in heterologous hosts (7-11). Often these proteins have problems with inclusion body formation, thereby decreasing the yield of pharmaceutically important products. Single amino acid substitutions can affect the folding pathway by shifting the folding from the productive pathway to off-pathway aggregation. For example, the amino acid substitutions in transthyretin causes a shift in the equilibrium between the native state and an aggregation-prone unfolding intermediate, resulting in amyloid formation. Individuals with any of the 50 known amino acid substitutions in transthyretin are predisposed to familial amyloidosis (12-15). During the folding of P22 tailspike proteins with tsf (te...

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“…The roles played by specific mutations in the action spectra of TEM ␤-lactamases were analyzed previously and described in different papers (4,13,27,43,48). The new bla TEM-95b (P3) gene renders a ␤-lactam resistance phenotype similar to those of other isolates in this study with a TEM-1-type ␤-lactamase.…”

Section: Discussionmentioning

confidence: 99%

β-Lactamases in Ampicillin-ResistantEscherichia coliIsolates from Foods, Humans, and Healthy Animals

Briñas

Zarazaga

Sáenz

et al. 2002

Antimicrob Agents Chemother

262

132

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, and OXA-type ␤-lactamases were studied by PCR with 124 ampicillin-resistant (AMP r ) Escherichia coli isolates recovered from foods of animal origin (n ‫؍‬ 20) and feces of humans (n ‫؍‬ 49) and healthy animals (n ‫؍‬ 55). PCR showed that 103 isolates were positive for TEM and negative for SHV and OXA. Three E. coli isolates showed a positive reaction for OXA, and one showed a positive reaction for SHV. The remaining 17 E. coli isolates were negative for the three enzymes by PCR. Fifty-seven of the 103 bla TEM amplicons were sequenced. Different molecular variants of bla TEM-1 were found in 52 isolates: bla TEM-1a (n ‫؍‬ 9), bla TEM-1b (n ‫؍‬ 36), bla TEM-1c (n ‫؍‬ 6), and bla TEM-1f (n ‫؍‬ 1). Four inhibitor-resistant TEM (IRT) ␤-lactamase-encoding genes were also detected: bla TEM-30c (IRT-2), bla TEM-34b (IRT-6), bla TEM-40b (IRT-11), and bla TEM-51a (IRT-15). A new bla TEM gene, named bla TEM-95b , which showed a mutation in amino acid 145 (P3A) was detected. It was found in a food isolate of chicken origin (AMP r , amoxicillin-clavulanic acid susceptible). The promoter region in 24 bla TEM amplicons was analyzed, and the weak P3 promoter was found in 23 of them (bla TEM-1 in 20 amplicons and bla TEM-51a , bla TEM-30c , and bla TEM-95b in 1 amplicon each). The strong Pa/Pb promoter was found only in the bla TEM-34b gene. No extended-spectrum ␤-lactamases were detected. Mutations at position ؊42 or ؊32 in the ampC gene promoter were demonstrated in 4 of 10 E. coli isolates for which the cefoxitin MIC was >16 g/ml. Different variants of bla TEM-1 and IRT bla TEM genes were found among the AMP r E. coli isolates from foods and the feces of humans and healthy animals, and a new gene, bla TEM-95b (P3), was detected.

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A secondary drug resistance mutation of TEM-1 β-lactamase that suppresses misfolding and aggregation

Cited by 79 publications

References 40 publications

Molecular Analyses of TEM Genes and Their Corresponding Penicillinase-Producing Neisseria gonorrhoeae Isolates in Bangkok, Thailand

Molecular Analyses of TEM Genes and Their Corresponding Penicillinase-Producing Neisseria gonorrhoeae Isolates in Bangkok, Thailand

Alleviation of a Defect in Protein Folding by Increasing the Rate of Subunit Assembly

β-Lactamases in Ampicillin-ResistantEscherichia coliIsolates from Foods, Humans, and Healthy Animals

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