The antibiotic action of methylarsenite is an emergent property of microbial communities

Abstract

Arsenic is the most ubiquitous environmental toxin.Here, we demonstrate that bacteria have evolved the ability to use arsenic to gain a competitive advantage over other bacteria at least twice. Microbes generate toxic methylarsenite (MAs(III)) by methylation of arsenite (As(III)) or reduction of methylarsenate (MAs(V)). MAs(III) is oxidized aerobically to MAs(V), making methylation a detoxification process. MAs(V) is continually re-reduced to MAs(III) by other community members, giving them a competitive advantage over sensitive bacteria. Because generation of a sustained pool of MAs(III) requires microbial communities, these complex interactions are an emergent property. We show that reduction of MAs(V) by Burkholderia sp. MR1 produces toxic MAs(III) that inhibits growth of Escherichia coli in mixed culture. There are three microbial mechanisms for resistance to MAs(III). ArsH oxidizes MAs(III) to MAs(V). ArsI degrades MAs(III) to As(III). ArsP confers resistance by efflux. Cells of E. coli expressing arsI, arsH or arsP grow in mixed culture with Burkholderia sp. MR1 in the presence of MAs(V). Thus MAs(III) has antibiotic properties: a toxic organic compound produced by one microbe to kill off competitors. Our results demonstrate that life has adapted to use environmental arsenic as a weapon in the continuing battle for dominance.

The Arsenic Methylation Cycle: How Microbial Communities Adapted Methylarsenicals for Use as Weapons in the Continuing War for Dominance

“…To date, more and more bacterial strains have been identified that are capable of reducing MAs(V), including the environmental isolate Burkholderia sp. MR1, P. putida KT2440, S. putrefaciens 200, and Sinorhizobium meliloti RM1021 (Chen et al, 2019b). However, the genes/enzymes involved in MAs(V) reduction have still not been identified.…”

“…Like most antibiotics, it would have required a way to get out the cells of the producer, and the ArsP MAs(III) efflux permease also appears to have evolved prior to the GOE. Other bacteria acquired the arsP gene and became resistant to MAs(III) -an early example of antibiotic resistance (Chen et al, 2019b). Although cells with arsM would also have produced DMAs(III), when arsP is co-expressed, it extrudes MAs(III) before it can be methylated a second time (Chen et al, 2019b), so the more stable MAs(III) would have been the major species with antibiotic activity.…”

“…Other bacteria acquired the arsP gene and became resistant to MAs(III) -an early example of antibiotic resistance (Chen et al, 2019b). Although cells with arsM would also have produced DMAs(III), when arsP is co-expressed, it extrudes MAs(III) before it can be methylated a second time (Chen et al, 2019b), so the more stable MAs(III) would have been the major species with antibiotic activity. After the GOE, MAs(III) was oxidized to less toxic MAs(V).…”

“…Two microbially-generated methylarsenicals, MAs(III) and the arsenic-containing amino acid AST, have recently been shown to have antimicrobial properties and have been proposed to be true antibiotics (Chen et al, 2019b;Nadar et al, 2019). First, even though As(III) is itself toxic, MAs(III), the first product during the arsenic methylation pathway catalyzed by the widespread enzyme As(III) methyltransferase (orthologs are termed ArsM in microbes and AS3MT in animals), is generally more toxic than inorganic As(III).…”

Arsenic and the gastrointestinal tract microbiome

“…The ability to utilize As(III) or As(V) for energy generation would provide a distinct advantage. Furthermore, production of a toxin such as MAs(III) by even a low abundance organism could have devastating effects on microbiome neighbours that lack the ability to eliminate it from the cell (ArsP) or detoxify it (ArsI or ArsH) (Chen et al, 2018). Production of arsenic-based antibiotics such as arsinothricin (Kuramata et al, 2016) could have similar effects, though moderated by ArsN that inactivates it (Nadar et al, 2019) and arsenic resistance acquired from spontaneous mutations in vivo will also account for some changes.…”