Drug metabolism and antibiotic resistance in micro‐organisms

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This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro‐organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc

The identification of the importance of the gut microbiome and the possibility of controlling the gut microbiome and its metabolism in disease is an important new avenue for research, opening up novel possibilities for antimicrobial strategies. The role of the gut bacteria in the metabolism of orally administered drugs is relatively under investigated, and in the future, this may represent an important facet of personalized medicine.

There are two classes of drug‐metabolizing enzymes in bacteria discussed in this themed section: the azoreductases (Ryan, 2017) and the arylamine N‐acetyltransferases (Kubiak et al., 2017). The azoreductases, which are found in gut bacteria, activate azo prodrugs, such as balsalazide, used in inflammatory bowel disease and also the nitrofuran group of antibiotics. The azoreducatse flavoenzymes use the same mechanism to catalyse the release of the active component 5‐aminosalicylate from the azo compound balsalazide or the formation of a highly reactive hydroxyamino group in nitrofurazone. The review (Ryan, 2017) also highlights the human equivalent of the azoreductases and the role of Single Nucleotide Polymorphisms in controlling its activity. The other bacterial drug‐metabolizing enzymes discussed are the arylamine N‐acetyltransferases, which acetylate arylamine and hydrazine drugs. These enzymes were initially studied in humans as they are important in the inactivation of the anti‐tubercular agents isoniazid and p‐aminosalicylate. The bacterial enzymes also acetylate 5‐aminosalicylate released from azo pro drugs by azoreductase.

N‐acetyltransferases have been found in a range of micro‐organisms in the microbiome, as well as in mycobacteria and other pathogens. A unique arylamine N‐acetyltransferase from Bacillus anthracis is described by Kubiak et al. (2017). The enzyme is encoded by one of three arylamine N‐acetyltransferase genes in the organism, and the authors show how the activity is controlled by the shorter C terminus compared with most isoenzymes and also through an unusual active site catalytic triad (Cys‐His‐Glu), which is present in this enzyme compared with almost all other members of the enzyme class, which have Cys‐His‐Asp.

The theme of drug metabolism is also highlighted in a study of the anti‐mycobacterial action of a series of piperidinols (Guy et al., 2017), which were first identified as inhibitors of mycobacterial arylamine N‐acetyltransferases. As well as acetylating isoniazid, N‐acetyltransferase has also been demonstrated to have an endogenous role in mycobacteria in relation to cell wall synthesis, which makes it a good candidate target for antimicrobial action. Guy et al. (2017) discuss the range of activities of the piperidinols in specifically inhibiting mycobacterial growth and reach the conclusion that there are multiple targets for these compounds in mycobacteria.

This themed section also covers antibiotic resistance, the importance of which cannot be overemphasized as a risk to the future of human and animal health. Despite government initiatives, the challenge is relatively under resourced. Short‐term drug treatment of bacterial and yeast infection compared with prolonged treatment regimens such as in cancer, transplantation and neurodegenerative diseases means anti‐infectives cannot match financial returns on treatment of chronic conditions. However, urological and respiratory infections in the elderly and the risk of infection during chemotherapy and immunosuppression, for example, underline the need to curb infection as an adjunct to treating chronic conditions.

The ease of availability of antibiotics online and as over‐the‐counter antibiotics in many developing countries are realities, which impinge on UK policies on prescribing antibiotics in the context of a digitally connected mobile global population.

The spread of antibiotic resistance in tuberculosis is recognized as a global emergency, and this theme is addressed. Modes of infection, which render Mycobacterium tuberculosis difficult to treat, include intracellular stages, and this is a key area for treating mycobacterial infection. The cholesterol degradation pathway supplies nutrients for intracellular M. tuberculosis, and mycobacterial cholesterol metabolism is discussed as providing a route for targeting intracellular infection by M. tuberculosis (Abuhammad, 2017). A particular cholesterol degradation pathway, which is essential for intracellular survival of M. tuberculosis, provides an opportunity to explore a specific target, namely a C–C bond hydrolase known as HsaD, and the identification of HsaD inhibitors by a fragment‐based structural approach demonstrates that this is a useful target (Ryan et al., 2017).

Challenges associated with treating intracellular bacteria in relation to the different cellular barriers that must be crossed in order to treat intraphagosomal bacteria have also been discussed (Kamaruzzaman et al., 2017). The bacteria involved include M. tuberculosis but also the typhoid‐associated Salmonella enterica. On occasions, Staphylococcus aureus , which is particularly troublesome in relation to antibiotic resistance, can be intracellular with the release of intracellular organisms in skin infections leading to septicaemia. To overcome the different cellular barriers, approaches for treating infection include the development of nanoparticles, anti‐microbial peptides, anti‐sense oligonucleotides, which control gene expression through targeting RNA, and also novel use of a topical antibacterial polymer polyhexamethylene biguanide.

The formation of biofilms presents problems for treating bacterial infection, and approaches to either inhibit or prevent biofilm formation using light treatment as well as chemical and biological means through bacteriophage are reviewed (Hughes and Webber, 2017).

Vaccination has been a very successful health strategy in infection. And the article by da Silva et al. (2017) describes the importance of post‐translational modification in the transport of a vaccine antigen (factor H binding protein) to the cell surface of Neisseria meningitides. Reduced levels of factor H binding protein on the bacterial cell surface will, in some strains, render the vaccine ineffective. This study sheds light on the molecular basis behind these variations and proposes potential new antibacterial strategies.

Conflict of interest

The authors wish to acknowledge that they are co‐authors of the article by Ryan et al. (2017). Ryan is also an author of a review (Ryan, 2017) and a co‐author of the paper by Da Silva et al. 2017.

Sim, E. , and Ryan, A. (2017) Drug metabolism and antibiotic resistance in micro‐organisms. British Journal of Pharmacology, 174: 2159–2160. doi: 10.1111/bph.13839.