Abstract
Damage in genetic material is induced through the action of several drugs (directly or indirectly). Specially, antimicrobials from quinolone class (such as ciprofloxacin) induce DNA damage that promotes the formation of the RecA filament leading to auto-cleavage of LexA and allows the expression of SOS genes, including the error-prone polymerase (like umuC). The SOS pathway plays a critical role in the acquisition of mutations that lead to the emergence of antibiotic-resistant bacteria and the spread of virulence factors. This chapter provides a comprehensive review about the SOS response of Staphylococcus aureus and the modulatory effects of new compounds (natural or synthetics) on this pathway. The effects of some SOS inhibitors are highlighted such as baicalein and aminocoumarins. Compounds able to prevent SOS response are extremely important to develop new combinatory approaches to inhibit S. aureus mutagenesis. The study of new SOS inductors could reveal new insights into the pathways used by S. aureus to acquire drug resistance; examples of these compounds are the lysine-peptoid hybrid LP5, cyclic peptide inhibitors, etc. These studies can impact the development of new drugs. In conclusion, we hope to provide essential information about the effects of compounds on SOS response from S. aureus.
Keywords
- DNA damage
- mutagenesis
- virulence factors
- small colony variants
1. Introduction
Drug resistance is a well-known problem involved in the treatment of bacterial infections and its incidence is escalating in an alarming rate [1–3]. As a result, microbial diseases are still among the most serious problems to public health system, especially in developing countries where infectious diseases still represent a major cause of human mortality. Especially alarming is the rapid global spread of multiresistant bacteria that cause common infections and that resist treatment with existing antimicrobial medicines [4, 5]. The classical paradigm suggests that antibiotic resistance emerges by selection of preexisting mutants in the bacterial population exposed to antibiotics [1]. In contrast, recent data suggested that mutations evolve after cells encounter antibiotic therapy. This kind of mutation is known as adaptive mutation, which is activated by the SOS DNA repair and mutagenesis pathways [6, 7].
The SOS system is the bacterial DNA damage response that is activated by DNA damage or stalled DNA replication caused by the exposure of bacteria to stressful conditions [8] such as antibiotic treatment [9], starvation [10], and oxidative stress [11]. Repair of damaged DNA is critical for bacterial survival, and during this process, some mutations may be introduced into the genome, which may result in bacterial drug resistance [12, 13]. Accumulation of single-stranded DNA (ss-DNA) is the signal that induces the SOS response by promoting the formation of the RecA filament, which in turn activates the auto-cleavage activity of LexA and allows expression of several genes [8]. The SOS response is a very orchestrated pathway by which the bacterial cell improves its capacity to inhibit cell division, repair DNA, and express error-prone DNA polymerases to replicate noninstructive DNA lesions [14]. This pathway has been widely studied in
2. Overview of SOS response in Staphylococcus aureus
Since DNA damage may occur as a result of environmental agents and drugs, the role of SOS pathway in different conditions has been studied in
2.1. SOS response affects the expression of virulence factors in Staphylococcus aureus
To prove this concept, the effects of SOS response in the dissemination of pathogenicity island-encoded virulence factors in staphylococci was evaluated [22].
2.2. SOS response and mutagenesis in Staphylococcus aureus
Apart from its capacity to express virulence factors,
2.3. Induction of SOS increases the frequency of small colony variants in Staphylococcus aureus
Recently, the activation of SOS response was linked with the enhanced incidence of small colony variants (SCVs) in
On the other hand, mutations in genes related to menadione or hemin synthesis result in electron transport-defective strains as bacteria are unable to produce menaquinone and cytochromes, respectively [46, 47]. SCVs auxotrophic for menadione or hemin are resistance to aminoglycosides (such as gentamicin) due to a decrease in drug uptake [48]. Fluoroquinolones and mitomycin C Sub-MIC increased the generation of gentamicin-resistant SCVs with an increased mutation rate through activation of the SOS response [23]. The SOS response is also essential for the adaptation of
3. New compounds able to modulate the SOS response in Staphylococcus aureus
Given the role of SOS response in
Special attention has been given to the use of SOS inhibitors as therapeutic adjuvants in combating bacterial infections. These approaches involve inhibiting the SOS-mediated mutagenesis induced by drugs and thus improving their long-term viability. In these cases, LexA and RecA represent potential targets [53, 54]. In fact, the number of SOS inhibitors is still limited and most of the studies use
In a later study, the effects of novobiocin in the SOS response induced by ciprofloxacin were evaluated. Novobiocin is an aminocoumarin, a class of antibiotics that interferes with ATPase activity of the gyrase subunit B and the topoisomerase IV subunit ParE without inducing double-strand breaks [60–62]. Differently from quinolones, aminocoumarin treatment does not activate SOS response. In fact, novobiocin inhibited the
The concept that SOS response is a potential target was additionally explored using antimicrobial photoinactivation. Antimicrobial photodynamic therapy (aPDT) is a promising strategy for the treatment of localized infections, such as acne inflammation [63], periodontal, and peri-implant diseases [64]. aPDT consists in the use of three elements (photosensitizer agent, visible light, and oxygen), where the damage of different bacterial structures (cell envelopes, lipids, proteins, and DNA) would avoid the development of resistance [65]. The role of DNA damage and SOS response during photoinactivation was recently established. Different exogenous photosensitizers induced DNA damage and consequently the expression of
SOS response in
4. Conclusion
The SOS response is an essential pathway for
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