Researchers from the University of Antwerp screened 17939 assembled metagenomic samples from 21 different biomes, varying in sequencing quality and depth, over 46 countries, across 6 continents, for a period of 14 years (2005-2019) for clinically crucial antibiotic resistance genes (ARGs) commonly found in human biomes, anthropogenic biomes, and natural biomes such as freshwater, marine, and sediment. The study identifies checkpoint biomes in which interventions designed to disrupt clinically relevant mobile ARGs are likely to significantly reduce their dissemination and global burden in the long run.

According to the World Health Organization (WHO), antibiotic resistance is reaching an alarmingly high level worldwide. New resistance mechanisms are unwinding and spreading over the world, posing a threat to our ability to treat common infectious diseases. As antibiotics become less efficient, a rising number of infections are becoming more difficult, if not impossible, to cure.

ARGs are mobile genetic elements that are frequently found on plasmids or transposons. They can be passed from one cell to another by horizontal transmissions such as conjugation, transformation, or transduction. This gene exchange allows resistance to spread quickly within a bacterial community and among diverse kinds of bacteria. Antibiotic resistance presents substantial issues for clinicians who treat infectious infections. The massive number of antibiotics routinely released into the environment may create a selection to govern the spread and fate of ARGs across biomes; according to a recent analysis, 53,800 tonnes of antibiotics were released into the environment in China alone in 2013.

Over the last few decades, metagenomic data from various biomes has been deposited in public repositories. These metagenomic datasets give us a glimpse into conducting global surveillance of some of the most important mobile ARGs in human and animal health,

1) mobile colistin resistance genes (mcr genes) – Mobile colistin resistance (mcr) was first discovered in Escherichia coli of swine origin in China. The mcr genes encode enzymes conferring resistance to colistin, an antibiotic used as a last option for the treatment of infections caused by multidrug-resistant Gram-negative bacteria (GNB).

2) carbapenem resistance genes (CR genes) – Carbapenems have broad anti-bacterial activity and a unique structure defined by a carbapenem connected to a -lactam ring, which protects against most lactamases. Carbapenems are regarded as one of the most dependable medications for treating bacterial infections. The establishment and spread of resistance to these antibiotics, such as difficulty treating an infection with Carbapenem-Resistant Enterobacteriaceae, poses a severe public health problem.

3) beta-lactamase genes (BL genes) – Extended-Spectrum β-Lactamases (ESBL) genes produce enzymes that confer resistance to third-generation beta-lactam antibiotics, one of the most regular antibiotic classes.

With the facts laid out, the authors set on to propose three scenarios to identify the global distribution of ARGs: 

(1) ARGs propagate and disperse internationally by physical and biological forces, including human movement, which can lower geographic barriers with horizontal gene transfer weakening genetic barriers and encouraging ARG global expansion.

(2) Ecological processes such as biotic and abiotic selection and interactions determine the distribution and dissemination of ARGs-harboring microorganisms. 

(3) Stochastic mechanisms, such as random microbial birth/death events, spontaneous microbial colonization, ecological drift, and environmental perturbation, make the distribution of ARGs random.

To address this, the current study involves a thorough screening of publicly available and global metagenomic datasets (deposited till October 2019) in order to create a landscape of the distribution of mcrCR, and BL/ ESBL genes. Researchers also investigated multiple biomes globally, representing various antibiotic use hotspots. 

The distribution of mcr and CR genes is determined by ecological boundaries

Ecological barriers with varying abiotic and biotic properties for niche microbes may also influence the migration of ARGs-carrying microorganisms worldwide. Furthermore, the fitness costs imposed by resistance gene acquisition and out-competition by antibiotic-resistant bacteria may increase the potential exclusion of migrating microorganisms in the new habitat, increasing the effects of ecological limits. The current result that the individual impacts of biomes and possible hosts and their combined effects had the most significant influence on ARG distribution underscores the importance of ecological boundaries in ARG dispersal. 

Our findings on prospective hosts broaden the previous discovery from specific biomes to more diversified biomes. The null model results revealed that the distribution of ARGs was controlled by deterministic processes rather than stochastic processes, indicating the necessity of ecological boundaries. Surprisingly, anthropogenic causes had only a minor impact on ARG distribution. ARGs were also discovered to be most numerous in wastewater, making it a hotspot for ARGs exchange. Wastewater contains antibiotics, disinfectants, metals, and nutrients from various settings, increasing bacteria and ARGs’ diversity.

ARGs may be transmitted across biomes

The proportions of ARG transfer were higher in biomes with similar characteristics, such as the human gut and oral, and between wastewater and bioreactor. Transmission proportions were found to be relatively low among biomes with distinct features. Lin et al. findings .’s show that natural biomes, rather than artificial biomes, are the most likely source biomes for human-acquired ARGs.

Mcr-9 was discovered in food, human stomach, human skin, fermentation, and bioreactor, implying that this ARG might be transmitted across these biomes via plasmids. Only mcr-3 was discovered in wastewater and freshwater, in addition to mcr-9. Surprisingly, blaTEM-116, a broad-spectrum beta-lactamase encoding beta-lactamases, had the most significant dispersion among the genes tested. Most of the blaTEM-116 hosting scaffolds found in the human gut were likely housed by Corynebacterium species, some of which are known opportunistic human infections. The genetic backgrounds were also ascribed to the probable transmission of blaOXA-233, blaGES-2, blaGES-15, and blaKPC-2 across biomes, as most scaffolds encoding these genes were mediated by plasmids and IS (Insertion Sequence) elements, and were likely hosted by microbes with a broad niche.

Limitations

The global-scale surveillance research of ARGs has drawbacks, such as uneven sequencing quality, depth, and sample sizes between years, countries, and biomes, which still need to be solved for studies relying on global datasets. Due to a lack of complete datasets, the examination of the effects of anthropogenic factors on ARG distribution could not include critical aspects such as sanitation and drinking water supply, which should be considered in future studies.

Researchers thus discovered that the global distribution of ARGs follows a non-random pattern that is mainly driven by the biomes where they and their possible host species co-exist, with transmission occurring preferentially between biomes with similar traits limited by ecological boundaries. Notably, the identification of checkpoint biomes with an aim to disrupt clinically relevant mobile ARGs are most likely to be the most effective step in lowering propagation and their worldwide burden.

Article Sources: Reference paper

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Shwetha is a consulting scientific content writing intern at CBIRT. She has completed her Master’s in biotechnology at the Indian Institute of Technology, Hyderabad, with nearly two years of research experience in cellular biology and cell signaling. She is passionate about science communication, cancer biology, and everything that strikes her curiosity!

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