Abstract
Many antibiotics, either directly or indirectly, cause DNA damage thereby activating the bacterial DNA damage (SOS) response. SOS activation results in expression of genes involved in DNA repair and mutagenesis, and the regulation of the SOS response relies on two key proteins, LexA and RecA. Genetic studies have indicated that inactivating the regulatory proteins of this response sensitizes bacteria to antibiotics and slows the appearance of resistance. However, advancement of small molecule inhibitors of the SOS response has lagged, despite their clear promise in addressing the threat of antibiotic resistance. Previously, we had addressed this deficit by performing a high throughput screen of ∼1.8 million compounds that monitored for inhibition of RecA-mediated auto-proteolysis of Escherichia coli LexA, the reaction that initiates the SOS response. In this report, the refinement of the 5-amino-1-(carbamoylmethyl)-1H-1,2,3-triazole-4-carboxamide scaffold identified in the screen is detailed. After development of a modular synthesis, a survey of key activity determinants led to the identification of an analog with improved potency and increased breadth, targeting auto-proteolysis of LexA from both E. coli and Pseudomonas aeruginosa. Comparison of the structure of this compound to those of others in the series suggests structural features that may be required for activity and cross-species breadth. In addition, the feasibility of small molecule modulation of the SOS response was demonstrated in vivo by the suppression of the appearance of resistance. These structure activity relationships thus represent an important step toward producing Drugs that Inhibit SOS Activation to Repress Mechanisms Enabling Resistance (DISARMERs).
Highlights
Antibiotic resistant bacteria represent one of the most pressing issues in infectious disease research today (Brown and Wright, 2016)
In the initial high throughput screen (HTS), the parent 5-amino1-(carbamoylmethyl)-1H-1,2,3-triazole-4-carboxamide, 1, had an IC50 value of 32 μM (Table 1). This chemotype was well behaved in the HTS, producing close to 100% inhibition, and appeared to offer the most chemical tractability to allow for the construction of structure activity relationships (SARs)
A important consideration was the chemical tractability of the lead compound, which permitted the development of a highly modular synthesis that allowed for an initial survey of structure-activity relationships
Summary
Antibiotic resistant bacteria represent one of the most pressing issues in infectious disease research today (Brown and Wright, 2016). A promising alternative approach is to target pathways that promote acquired resistance to antibiotics. One such pathway is the bacterial DNA damage response pathway, known as the SOS response (Figure 1). The SOS response is well conserved across pathogens and involves numerous genes (e.g., >40 in Escherichia coli) These proteins include translesion DNA polymerases that promote mutagenesis, recombinases that mobilize antibiotic resistance genes, and proteins that mediate persistence, biofilm formation or directly promote antibiotic evasion (McKenzie et al, 2000; Beaber et al, 2004; Schlacher et al, 2006; Galhardo et al, 2007; Da Re et al, 2009; Dörr et al, 2009, 2010; Gotoh et al, 2010). Suppression of the SOS pathway would be predicted to compromise the response of bacteria to antibiotics
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