**1. Introduction**

"*What is essential is invisible to the eye*". Antoine de Saint-Exupéry. "The Little Prince" (1943) [1].

Antibiotic-resistant bacteria caused 1.27 million human deaths worldwide in 2019 [2]. This estimation indicates, once more, that antimicrobial resistance is a severe world health problem [3,4]. Bacterial pathogens are, by definition, the etiological agents of bacterial diseases. However, one must consider commensal bacteria in the list of public health concerns because they are also reservoirs of genes encoding adaptive traits (non-housekeeping genes), e.g., virulence, heavy-metal resistance, and antibiotic-resistance genes that can transfer to pathogenic bacteria [5–11]. For example, a recent work involving bacteria of the *Neisseria* genus has shown that the phenotypic resistance profile of four commensal *Neisseria* species was higher than that of four pathogenic *Neisseria gonorrhoeae* strains [12].

Gene transfer occurs through three major mechanisms. Bacteria can directly uptake DNA from the environment or with the connivance of vectors such as conjugative plasmids, conjugative integrative elements, or bacteriophages [13,14]. For example, in a study of the donor ability of a naturally isolated conjugative plasmid conferring resistance to six antibiotics between 14 enterobacteria, the best plasmid donor was a commensal *Escherichia coli* [7].

These DNA transfer events may occur between different bacteria within microbiomes. Human microbiomes–the collection of all microorganisms (and their genomes) living in

**Citation:** Dionisio, F.; Domingues, C.P.F.; Rebelo, J.S.; Monteiro, F.; Nogueira, T. The Impact of Non-Pathogenic Bacteria on the Spread of Virulence and Resistance Genes. *Int. J. Mol. Sci.* **2023**, *24*, 1967. https://doi.org/10.3390/ ijms24031967

Academic Editor: Maria Teresa Mascellino

Received: 30 November 2022 Revised: 11 January 2023 Accepted: 16 January 2023 Published: 19 January 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

human tissues–are complex [15], comprising more than 10<sup>13</sup> bacterial cells belonging to hundreds of species [16]. In the human body, microorganisms are especially numerous and diverse in the skin, mucosa, and gastrointestinal tract, possibly comprising both pathogenic and non-pathogenic bacteria [17]. The metagenome refers to the set of all genes in a microbiome, including chromosomal genes and extra-chromosomal genetic elements, e.g., bacteriophages, transposons, plasmids, and other mobile genetic elements. Several microbiomes can also be very complex, namely that of other animals, soil, plant roots, sewage, etc.

Generally, in human and veterinary medicine, the onset of a symptomatic infectious disease leads to the prescription of antibiotics. However, we argue here that this does not necessarily mean that bacterial pathogenicity is directly associated with antibiotic resistance (see next sections).

Consider the following arguments:


Readers that feel some of these arguments are accurate should keep reading this paper. The vast majority of microorganisms in human microbiomes are non-pathogenic, and we will see how they might play critical roles in the spread of virulence and resistance genes. Paraphrasing Antoine de Saint-Exupéry [1], what is essential, is often unnoticed.
