Tackling Multidrug Resistance in Streptococci - From Novel Biotherapeutic Strategies to Nanomedicines

Abstract

The pyogenic streptococci group includes pathogenic species for humans and other animals and has been associated with enduring morbidity and high mortality. The main reason for the treatment failure of streptococcal infections is the increased resistance to antibiotics. In recent years, infectious diseases caused by pyogenic streptococci resistant to multiple antibiotics have been raising with a significant impact to public health and veterinary industry. The rise of antibiotic-resistant streptococci has been associated to diverse mechanisms, such as efflux pumps and modifications of the antimicrobial target. Among streptococci, antibiotic resistance emerges from previously sensitive populations as result of horizontal gene transfer or chromosomal point mutations due to excessive use of antimicrobials. Streptococci strains are also recognized as biofilm producers. The increased resistance of biofilms to antibiotics among streptococci promote persistent infection, which comprise circa 80% of microbial infections in humans. Therefore, to overcome drug resistance, new strategies, including new antibacterial and antibiofilm agents, have been studied. Interestingly, the use of systems based on nanoparticles have been applied to tackle infection and reduce the emergence of drug resistance. Herein, we present a synopsis of mechanisms associated to drug resistance in (pyogenic) streptococci and discuss some innovative strategies as alternative to conventional antibiotics, such as bacteriocins, bacteriophage, and phage lysins, and metal nanoparticles. We shall provide focused discussion on the advantages and limitations of agents considering application, efficacy and safety in the context of impact to the host and evolution of bacterial resistance.

Keywords: antimicrobial resistance; bacteriocins; bacteriophage; biofilms; nanomedicine; nanoparticles; pyogenic streptococci.

FIGURE 1

General genotypic and biochemical aspects of antibiotic resistance mechanisms.

FIGURE 2

Transformation is the process by which naked DNA from the external environment is incorporated into a bacterial cell. For this process is requires the recipient cell to exhibit on its membrane special DNA binding proteins. Transduction is the process by which a phage transfers DNA from one bacterial strain to another. Conjugation is the process mediated by cell-to-cell contact that provides direct DNA transfer. Conjugative transfer systems associated with plasmids usually code the necessary proteins to DNA exchange. The plasmids are kept as extra-chromosomal genetic material by external selective pressure (e.g., presence of metal or antibiotic). Overall, these mechanisms can be followed by recombination events that allow the genetic determinants to be inserted stably into the chromosome.

FIGURE 3

Different mechanism of action of metallic NPs in bacteria. Nanoparticles induce wide effects in bacterial metabolism by different approaches: (i) ROS generation: Ag, Fe, Cu, and Zn NPs induce ROS (reactive oxygen species), the ROS generated are highly reactive toward biological molecules such as proteins and DNA and interact and damage them. (ii) Damage membrane: Ag and Cu NPs interact with chemical groups of bacterial membrane (sulfate or phosphate) and disturb the normal functions. (iii) Drug and gene delivery systems: Au and Fe NPs could be carrier of gene moieties (DNA/RNA) that interact with bacterial gene, or deliver drug improving some pharmacodynamic parameters. (iv) Ribosome: Au NPs inhibit the union of transfer RNA (tRNA) to ribosome. (v) Photothermal therapy of Au NPs mediated by laser irradiation that disturb the membrane structure. (vi) Bacterial respiration: Ag NPs alter the electronic transport and inhibit the respiratory chain.