No abstract

Drug‐resistant bacteria are rapidly becoming a significant problem across the globe. One element that factors into this crisis is the role played by bacterial biofilms in the recalcitrance of some infections to the effects of conventional antibiotics. Bacteria within a biofilm are highly tolerant of both antibiotic treatment and host immune responses. Biofilms are implicated in many chronic infections, including tuberculosis, in which they can act as bacterial reservoirs, requiring an arduous antibiotic regimen to eradicate the infection. A separate, compounding problem is that antibiotics once seen as last‐resort drugs, such as the polymyxin colistin, are now seeing more frequent usage as resistance to front‐line drugs in Gram‐negative bacteria becomes more prevalent. The increased use of such antibiotics inevitably leads to an increased frequency of resistance. Drugs that inhibit biofilms and/or act as adjuvants to overcome resistance to existing antibiotics will potentially be an important component of future approaches to antibacterial treatment. We have previously demonstrated that analogues of the meridianin natural product family possess adjuvant and antibiofilm activities. In this study, we explore structural variation of the lead molecule from previous studies, and identify compounds showing both improved biofilm inhibition potency and synergy with colistin.

It has become evident that numerous infections are polymicrobial and Pseudomonas aeruginosa and Staphylococcus aureus are among the most frequently isolated co-infecting bacterial species. We applied mass spectrometry guided interaction studies to determine how chemical interaction shapes the fitness and community structure during co-infection of these two pathogens. We demonstrate that S. aureus is equipped with an elegant mechanism, inactivation of pyochelin via the yet uncharacterized methyltransferase Spm (staphylococcal pyochelin methyltransferase), to increase its survival during in vivo competition with P. aeruginosa. Methylation of pyochelin abolishes the siderophore activity of pyochelin and significantly lowers pyochelin-mediated intracellular ROS production in S. aureus. In a murine wound co-infection model, a S. aureus mutant unable to metyhlate pyochelin shows significant lower fitness compared to its parental strain.One-Sentence SummaryStaphylococcus aureus inactivates pyochelin to increase its survival during in vivo competition with Pseudomonas aeruginosa.

Biofilm growth is thought to be a significant obstacle to the successful treatment of Mycobacterium abscessus infections. A search for agents capable of inhibiting M. abscessus biofilms led to our interest in 2-aminoimidazoles and related scaffolds, which have proven to display antibiofilm properties against a number of Gram-negative and Gram-positive bacteria, including Mycobacterium tuberculosis and Mycobacterium smegmatis. The screening of a library of 30 compounds led to the identification of a compound, AB-2-29, which inhibits the formation of M. abscessus biofilms with an IC50 (the concentration required to inhibit 50% of biofilm formation) in the range of 12.5 to 25 μM. Interestingly, AB-2-29 appears to chelate zinc, and its antibiofilm activity is potentiated by the addition of zinc to the culture medium. Preliminary mechanistic studies indicate that AB-2-29 acts through a distinct mechanism from those reported to date for 2-aminoimidazole compounds.

Over the past decades, antibiotic resistance has grown to a point where orthogonal approaches to combating infections caused by resistant bacteria are needed. One such approach is the development of nonmicrobicidal small molecules that potentiate the activity of conventional antibiotics, termed adjuvants. The diterpene natural product 12(S),16ɛ-dihydroxycleroda-3,13-dien-15,16-olide, which we refer to as (À )-LZ-2112, is known to synergize with oxacillin against methicillinresistant Staphylococcus aureus (MRSA). To explore this activity, (À )-LZ-2112 was synthesized and the structure confirmed through X-ray analysis. Preliminary structure-activity relationship studies following the synthesis of several analogs identified key structural elements responsible for activity and indicate that scaffold simplification is possible. A preliminary mode of action study suggests mecA plays a role in the adjuvant activity of (À )-LZ-2112.