How Streptococcus suis escapes antibiotic treatments

Abstract

Streptococcus suis is a zoonotic agent that causes sepsis and meningitis in pigs and humans. S. suis infections are responsible for large economic losses in pig production. The lack of effective vaccines to prevent the disease has promoted the extensive use of antibiotics worldwide. This has been followed by the emergence of resistance against different classes of antibiotics. The rates of resistance to tetracyclines, lincosamides, and macrolides are extremely high, and resistance has spread worldwide. The genetic origin of S. suis resistance is multiple and includes the production of target-modifying and antibiotic-inactivating enzymes and mutations in antibiotic targets. S. suis genomes contain traits of horizontal gene transfer. Many mobile genetic elements carry a variety of genes that confer resistance to antibiotics as well as genes for autonomous DNA transfer and, thus, S. suis can rapidly acquire multiresistance. In addition, S. suis forms microcolonies on host tissues, which are associations of microorganisms that generate tolerance to antibiotics through a variety of mechanisms and favor the exchange of genetic material. Thus, alternatives to currently used antibiotics are highly demanded. A deep understanding of the mechanisms by which S. suis becomes resistant or tolerant to antibiotics may help to develop novel molecules or combinations of antimicrobials to fight these infections. Meanwhile, phage therapy and vaccination are promising alternative strategies, which could alleviate disease pressure and, thereby, antibiotic use.

Keywords: Streptococcus suis; antibiotic resistance; antibiotic tolerance; multidrug resistance; recalcitrance.

Figure 1

Historical development of resistance of S. suis to different antibiotic classes in A Europe, B Asia, and C America (North and South America). The graphs include data reported between 1987 and 2021 in scientific articles published in National Library of Medicine under search criterium ¨antimicrobial resistance and Streptococcus suis¨, and the antibiotic surveillance data from Denmark (DANMAP) and France (RESAPATH). For panel A, a total of 19 articles and 18 reports (DANMAP, RESAPATH) were used, and totals of 13 and 8 articles were used for panels B and C, respectively. For simplicity, the averages of the percentage of resistance to antibiotics of the same class were calculated for each report. Please note that not all the surveillance systems are using the same Epidemiological cut-off value ECOFFs; we followed the criteria used by authors. The evolution of the multidrug-resistance rate worldwide is depicted in D, taking into consideration a total of 20 scientific articles. Multiresistance was considered when an isolate was resistant to at least three antibiotics of different classes as declared by authors. Also, the average of the antimicrobial-resistance rate of different reports in the same year was used. The X-axes show the year of isolation.

Figure 2

Overview of the mode of action of antibiotics used to treat S. suis infections. According to its target site, antibiotics can be classified as A inhibitors of peptidoglycan (PG) synthesis by blocking penicillin-binding proteins (PBPs) (β-lactams) or binding D-Ala-D-Ala in the peptide chain of the PG precursor lipid II (glycopeptides), B inhibitors of ribosome function that bind to the ribosome 50S (macrolides, amphenicols, lincosamides, and pleuromutilins) or 30S (tetracyclines and aminoglycosides) subunits, C inhibitors of folic acid synthesis including sulfonamides and trimethoprim, and D inhibitors of DNA transcription and replication by interfering with DNA gyrase or topoisomerase IV (quinolones). In A, the process of the synthesis and transport of PG precursors is indicated. The 30S and 50S ribosome subunits and the A, P, and E sites are indicated in B. The A site is the binding site for charged tRNA molecules during protein synthesis. Then, the tRNA moves to the P site and its cargo is then linked to the growing polypeptide chain. Thereafter, the tRNA is moved to the E site for exit. The route for folate synthesis is shown in C. In D, the requirement for DNA gyrase and topoisomerase IV in DNA transcription and replication processes is shown. Antibiotics are indicated with colored stars. A red circle indicates resulting inhibition of the cellular process. Abbreviations: PABA, p-aminobenzoic acid; pteridine, 7,8-dihydro-6-hydroxymethylpterin-pyrophosphate; UDP, uridine diphosphate.

Figure 3

Chemical structure of diverse antibiotics.