Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success

The fluoroquinolone antibacterials: past, present and future perspectives

Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc1 complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1574-6976.2010.00247.x

Quinolones: from antibiotics to autoinducers

A new perspective on the topic of antibiotic resistance is beginning to emerge based on a broader evolutionary and ecological understanding rather than from the traditional boundaries of clinical research of antibiotic-resistant bacterial pathogens. Phylogenetic insights into the evolution and diversity of several antibiotic resistance genes suggest that at least some of these genes have a long evolutionary history of diversification that began well before the 'antibiotic era'. Besides, there is no indication that lateral gene transfer from antibiotic-producing bacteria has played any significant role in shaping the pool of antibiotic resistance genes in clinically relevant and commensal bacteria. Most likely, the primary antibiotic resistance gene pool originated and diversified within the environmental bacterial communities, from which the genes were mobilized and penetrated into taxonomically and ecologically distant bacterial populations, including pathogens. Dissemination and penetration of antibiotic resistance genes from antibiotic producers were less significant and essentially limited to other high G+C bacteria. Besides direct selection by antibiotics, there is a number of other factors that may contribute to dissemination and maintenance of antibiotic resistance genes in bacterial populations.

https://orbit.dtu.dk/files/97087575/FEMSLE_757.PDF

Evolution and ecology of antibiotic resistance genes

The quinolones have evolved from antibacterial agents with a limited spectrum of predominantly anti-Gram-negative antimicrobial activity and a restricted number of indications to a class of widely used oral (and, in some cases, intravenous) antibiotics with extensive indications for infections caused by many bacterial pathogens in most body tissues and fluids. This evolutionary pattern has arisen through the development of new core and side-chain structures, with associated improvements in activity, pharmacokinetics and tolerability, and through the selection of molecules that remain useful and well tolerated. This review describes the progress of the quinolones from the first to the third (IIIa and IIIb) generations. Special attention is given to gemifloxacin, currently the most developmentally advanced third-generation quinolone, which has enhanced in vitro Gram-positive antimicrobial activity and no troublesome adverse drug reactions. Preliminary data indicate that gemifloxacin should prove to be an important addition to the fluoroquinolone class. Further clinical trial data are awaited with interest.

Quinolone generations: natural history or natural selection?

Novel 1,8-naphthyridine derivatives having antibacterial activity and represented by the following general formula (I):
 wherein:
 R is a cyclic amino group which may have a substituent; and X is a halogen atom, and their pharmacologically acceptable salts and a process for their preparation are disclosed

1,8-naphthyridine derivatives

An optically active pyridobenzoxazine derivative re-presented by formula (I): (see formula I) wherein R1 and R2 wherein R1 and R2, which may be the same or different, each represent an alkyl group having from 1 to 6 carbon atoms, a halogenated alkyl group having from 1 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 6 carbon atoms; or an alkoxymethyl group having from 2 to 7 carbon atoms; R1 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, an acyl group having from 2 to 7 carbon atoms, a halogen-substituted or unsubstituted alkyloxy-carbonyl group having from 2 to 7 carbon atoms, a phenylmethyl-oxycarbonyl group, or a phenylmethyloxycarbonyl group whose phenyl moiety is substituted with a halogen atom, a nitro group, or a methoxy group; R4 represents a methyl or fluoro-methyl group which is in a .beta.-configuration; R5 represents a hydrogen atom, an amino group, a hydroxyl group, a methyl group, or a halogen atom; and X represents a fluorine atom or a chlorine atom, and a salt thereof are disclosed. These compounds exhibit potent antimicrobial activity with broad antimicrobial spectra and improved lipophilic properties.

O Daiichi Seiyaku Imamura

Papers

1,8-naphthyridine derivatives

Optically active pyridobenzoxazine derivatives