Un ecosistema malalt: la lluita contra la resistència a antibiòtics des d’una perspectiva global

La producció antropogènica d'antibiòtics ha provocat una malaltia dels ecosistemes microbians de dimensió planetària, la repercussió més immediata de la qual per a l'home és la intractabilitat de les infeccions. La comprensió del fenomen i les possibilitats d'intervenció requereixen nous mètodes conceptuals, analítics i tecnològics

Visceral Larva Migrans in Immigrants from Latin America

To determine whether increased migration is associated with an increase in incidence of toxocariasis (visceral larva migrans), we analyzed clinical data obtained from immigrants from Latin America. Although infection with Toxocara sp. roundworm larvae is distributed worldwide, seroprevalence is highest in tropical and subtropical areas

Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential beta-lactamase stable beta-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.Peer reviewe

In Vitro Selection of Variants Resistant to β-Lactams plus β-Lactamase Inhibitors in CTX-M β-Lactamases: Predicting the In Vivo Scenario?▿

CTX-M β-lactamases are the most prevalent group of enzymes within the extended-spectrum β-lactamases (ESBL). The therapeutic options for CTX-M-carrying isolates are scarce, forcing the reexamination of the therapeutic possibilities of β-lactams plus β-lactamase inhibitors (BBLIs). Inhibitor-resistant CTX-M β-lactamases (IR-CTX-M) have not hitherto been described in natural isolates. In this study, 168 cultures of the hypermutagenic Escherichia coli GB20 strain carrying plasmid pBGS18 with different blaCTX-M genes were submitted to parallel experimental evolution assays in the presence of increasing concentrations of a combination of amoxicillin and clavulanate. Fourteen CTX-M β-lactamases belonging to the three most representative clusters (CTX-M-1, -2, and -9) and the two main phenotypes (cefotaxime resistance and cefotaxime-ceftazidime resistance) were studied. Three types of IR-CTX-M mutants were detected, having mutations S130G, K234R, and S237G, which are associated with different resistance patterns. The most frequently recovered mutation was S130G, which conferred the highest resistance levels to BBLIs (reaching 12 μg/ml for amoxicillin-clavulanate and 96 μg/ml for piperacillin-tazobactam when acquired by CTX-M-1 cluster enzymes). The S130G change also provided a clear antagonistic pleiotropy effect, strongly decreasing the enzyme's activity against all cephalosporins tested. A double mutation, S130G L169S, partially restored the resistance against cephalosporins. A complex pattern observed in CTX-M-58, carrying P167S and S130G or K234R changes, conferred ESBL and IR phenotypes simultaneously. The K234R and S237G changes had a smaller effect in providing inhibitor resistance. In summary, IR-CTX-M enzymes might evolve under exposure to BBLIs, and the probability is higher for enzymes belonging to the CTX-M-1 cluster. However, this process could be delayed by antagonistic pleiotropy

Normal mutation rate variants arise in a Mutator (Mut S) Escherichia coli population.

The rate at which mutations are generated is central to the pace of evolution. Although this rate is remarkably similar amongst all cellular organisms, bacterial strains with mutation rates 100 fold greater than the modal rates of their species are commonly isolated from natural sources and emerge in experimental populations. Theoretical studies postulate and empirical studies teort the hypotheses that these "mutator" strains evolved in response to selection for elevated rates of generation of inherited variation that enable bacteria to adapt to novel and/or rapidly changing environments. Less clear are the conditions under which selection will favor reductions in mutation rates. Declines in rates of mutation for established populations of mutator bacteria are not anticipated if such changes are attributed to the costs of augmented rates of generation of deleterious mutations. Here we report experimental evidence of evolution towards reduced mutation rates in a clinical isolate of Escherichia coli with an hyper-mutable phenotype due a deletion in a mismatch repair gene, (ΔmutS). The emergence in a ΔmutS background of variants with mutation rates approaching those of the normal rates of strains carrying wild-type MutS was associated with increase in fitness with respect to ancestral strain. We postulate that such an increase in fitness could be attributed to the emergence of mechanisms driving a permanent "aerobic style of life", the negative consequence of this behavior being regulated by the evolution of mechanisms protecting the cell against increased endogenous oxidative radicals involved in DNA damage, and thus reducing mutation rate. Gene expression assays and full sequencing of evolved mutator and normo-mutable variants supports the hypothesis. In conclusion, we postulate that the observed reductions in mutation rate are coincidental to, rather than, the selective force responsible for this evolution

Emergence of ESBL-producing Escherichia coli ST131-C1-M27 clade colonizing patients in Europe

The ST131 Escherichia coli clone is associated with the global dissemination of ESBLs. It has been hypothesized that ST131 could take advantage of better colonizing abilities. However, the data on colonization prevalence of ESBL-ST131 in European hospitals are scarce

Distribution of the proportion of colonies with high and low mutation frequencies along four successive periods.

<p>On the top, distribution of <i>f</i> values in 20 colonies of the ancestor strain; below, distributions of <i>f</i> values in 45–51 colonies from 15 different passages belonging to each one of the 1^st (from 13^th to 53^rd passage), 2^nd (from 58^th to 93^rd passage), 3^rd (from 97^th to 138^th passage) and 4^th (from 141^st to 180^th passage) periods respectively. Black triangles and grey circles correspond to colonies with high- or low frequencies of mutation respectively.</p