al.2011). Furthermore, frequent co-existence of the blaNDM-gene on plasmids carrying genes encoding resistance to other classes of antibiotics like aminoglycosides and sulfamethoxazole (Moellering 2010; Nordmann 2011b) is being suggested to contribute to the selection and global spread of multi-drug resistance phenotype and thus, making blaNDM carrying E.coli a global public health concern.

2.17 Plasmid-Mediated quinolone  Resistance


Plasmid-mediated quinolone resistance was discovered in advertently

while studying ?-lactam resistance produced by a multi-resistance plasmid on transfer to a porin-deficient strain of . Ciprofloxacin resistance was evaluated as a control with the unexpected finding that it increased from 4 to 32 µg/ml on plasmid acquisition (Yamane K, et al. 2007).The increase in resistance was much less marked in  or  with intact porins, but the plasmid was readily transferred and decreased quinolone susceptibility in strains of Citrobacter, Salmonella, and even P. aeruginosa. The responsible resistance gene was named qnr, later amended to qnrA, as additional alleles were discovered. Investigation of a qnrA plasmid from Shanghai that conferred more than the expected level of ciprofloxacin resistance resulted in the discovery of a second plasmid-mediated mechanism: modification of certain quinolones by a particular aminoglycoside acetyltransferase, AAC (6 ?) – Ib-cr (Pe’richon B, Courvalin P, Galimand M 2007). The third mechanism of plasmid-mediated quinolone resistance (PMQR) was added with the discovery of plasmid-mediated quinolone efflux pumps QepA (Hansen LH, et al.  2007;  and Bouchakour M., Zerouali K., Claude J. D. P. G., et al. 2010; ) and OqxAB (Hooper D. C. 2010). In the last decade, PMQR genes have been found in bacterial isolates worldwide. They reduce bacterial susceptibility to quinolones, usually not to the level of clinical nonsusceptibility, but facilitate the selection of mutants with higher level quinolone resistance and promote treatment failure.

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2.18 Co-resistance to ?-lactams and (fluro) quinolones


                     Quinolone and fluoroquinolone antibiotics


Quinolones and fluoroquinolones represent another major class of antimicrobials which have been used successfully for the treatment of infections caused by E.coli in different settings (clinical as well as community ) (Ball 2000; FAO/WHO/OIE 2007). Being xenobiotics, the molecular structures of quinolone antibiotics have been adopted vis-a-vis their clinical requirements. Thus, the ‘naphthyroidine nucleus’ of nalidixic acid (Fig.2.3) has remained primarily conserved while a series of modified and more active compounds have been reported over the years. For example, fluorination at the sixth position has given rise to fluoroquinolones, and further modification of the side chains has led to increased activity against Gram-positive bacteria in addition to the Gram-negative ones (Ball 2000; Andriole 2005; Wiles et al.2010).


                                             Fig. 8: Ring structure of nalidixic acid

According to their antibacterial spectrum, the quinolone group of antibiotics have been classified into different generations (New Classification and Update on the Quinolone Antibiotics – May I, 2000 – American Academy of family Physicians, 2008). The only standard that has been applied for this classification includes the grouping of nonfluronited drugs (or simply the quinolones) within the first-generation and in general, the earlier generation agents tend to exhibit a narrower spectrum of activity than the later ones.

The antibacterial activity of (fluro)quinolones has been attributed to their ability to act as direct inhibitors of DNA synthesis. The inhibition occurs by targeting  – DNA gyrase, which is a gyrA and gyrB encoded tetrameric protein complex (GyrA2B2) and topoisomerase IV, which is a parC and pare encoded tetrameric protein complex (ParC2E2).Both the target proteins are encoded by the chromosomal genes but exhibit differential affinity for the different quinolone drugs (Hooper 2001a and b; Ince et al.2002). However, in each case, the quinolone bind to the enzyme-DNA complex and stabilize the DNA strand breaks created by the two enzymes. Subsequently, the progress of DNA replication fork is blocked by the antibiotic-DNA ternary complex. Thus, cytotoxic effects of fluoroquinolones occur by a two-step process which involves: 1) Conversion of the antibiotic-enzyme-DNA complex to an irreversible form; and 2) Generation and stabilization of the double-strand break in DNA (Hooper 2001a and b).

2.19 Mechanism underlying quinolone resistance

Despite their xenobiotic nature and early predictions of rare chances for emergence of bacterial resistance (Goldstein 1987; Sanders 1988), (fluro)quinolone resistance is being reported at an alarming rate (especially, among Enterobacteriaceae) (Garau et al.1999, Hooper 2001b; Karlowsky et al.2003). The levels of resistance have been higher for the narrow-spectrum quinolones e.g., nalidixic acid (ca. 15-20 %) than for the

           broad-spectrum fluoroquinolones (reaching up to 10%).

Resistance to quinolones can either be intrinsic or acquired

1) Intrinsic- resistance – observed as the innate susceptibility or resistance to antibiotics    

displayed by the occurring or wild-type bacterial species. For example, E.coli, pseudomonas aeruginosa and Staphylococcus aureus exhibit basal levels of expression of multi-drug efflux pumps (Hooper 2001a and b) which can accommodate a range of structurally unrelated antimicrobial compounds including (fluro)quinolone, ?-lactam, macrolide, aminoglycoside and tetracycline antibiotics or even dyes(Poole 2000; Hooper 2001a). One of the most well- studied representatives of the multi-drug efflux pumps imparting intrinsic resistance to quinolones among E.coli includes the AcrAB-Tol of E.coli (Ma et al. 1994).

2) Acquired resistance – may be mediated by mutations in the quinolone resistance-determining regions (QRDRs) of the chromosomally-encoded genes which alter target sites for quinolone namely DNA gyrase and topoisomerase IV, or it may also be mediated by one or more plasmid-mediated quinolone resistance (PMQR) genes (Ruiz 2003; Hopkins et al.2005;Rodriguez-Martinez et al.2011; Chen et al. 2012).The different PMQR genes identified among E.coli include: qnr(A-S)(encode proteins which interact with DNA gyrase and topoisomerase IV to prevent inhibition by quinolones), aac(6′) lb-cr encode a bifunctional enzyme variant of AAC(6′)-lb  which can acetylate aminoglycoside and fluoroquinolone viz. ciprofloxacin and norfloxacin but not moxifloxacin and Levofloxacin), qepAB and oqxAB (encode efflux pumps).

Besides these, there may still exist other known mechanisms of (fluro)quinolone resistance among E.coli strains because the known chromosomal-and plasmid-mediated mechanisms as well as presence of AcrAB multi-drug efflux pump have been detected in only 50-70% of the clinical isolates which display high-level quinolone resistance with MIC upto 1,500-fold higher than that expected in view of the known mechanisms. (Morgan-Linnell et al.2009).

Significance of co-resistance to ?-lactams and quinolones in waterborne E.coli

Broad-spectrum ?-lactams and quinolones have long formed the mainstay of successful treatment of infections caused by the different E.coli pathotypes (FAO/WHO/OIE,2007). Thus, the emergence and spread of co-resistance to both these classes of antibiotics may be regarded as a serious public health concern.

Occurrence of co-resistant E.coli strains especially, in the natural aquatic environments constitute a major concern because such environments provide ideal conditions to serve as a reservoir as well as a niche for the transfer of resistance genetic elements. Urban aquatic environments constantly subject to anthropogenic exposure may therefore readily promote the emergence and spread of multi-drug resistance phenotypes (Baquero et al. 2008; Zhang et al. 2009; Tacao et al. 2012). However, most studies which focus on the understanding of epidemiology as well as molecular mechanisms of co-resistance have been carried out with clinical strains either directly isolated from humans and animals

 (Lautenbach et al.2001; Fortini et al.2011; Shaheen et al.2012; Paltansing et al.2013; Ferjani et al.2014) or indirectly from the wastewaters discharged from hospitals (Diwan et al.2012; Adnan et al.2013; Chandran et al.2014). Since very little information is available regarding genes related to such co-resistance.

Since very little information is available regarding genes related to such co-resistance from the natural aquatic environments (Dhanji et al.2011; Alouache et al.2014; Zurfluh et al.2014; Tacao et al.2014), more studies are required to identify the quinolone resiatance determinants in E. coli strains which also encode the newer ?-lactamases.












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