Christian Melander

Inhibition of HIV fusion with multivalent gold nanoparticles.

The design and synthesis of a multivalent gold nanoparticle therapeutic is presented. SDC-1721, a fragment of the potent HIV inhibitor TAK-779, was synthesized and conjugated to 2.0 nm diameter gold nanoparticles. Free SDC-1721 had no inhibitory effect on HIV infection; however, the (SDC-1721)-gold nanoparticle conjugates displayed activity comparable to that of TAK-779. This result suggests that multivalent presentation of small molecules on gold nanoparticle surfaces can convert inactive drugs into potent therapeutics.

Combination approaches to combat multidrug-resistant bacteria.

The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants.

Small molecule control of bacterial biofilms

Bacterial biofilms are defined as a surface attached community of bacteria embedded in a matrix of extracellular polymeric substances that they have produced. When in the biofilm state, bacteria are more resistant to antibiotics and the host immune response than are their planktonic counterparts. Biofilms are increasingly recognized as being significant in human disease, accounting for 80% of bacterial infections in the body and diseases associated with bacterial biofilms include: lung infections of cystic fibrosis patients, colitis, urethritis, conjunctivitis, otitis, endocarditis and periodontitis. Additionally, biofilm infections of indwelling medical devices are of particular concern, as once the device is colonized infection is virtually impossible to eradicate. Given the prominence of biofilms in infectious diseases, there has been an increased effort toward the development of small molecules that will modulate bacterial biofilm development and maintenance. In this review, we highlight the development of small molecules that inhibit and/or disperse bacterial biofilms through non-microbicidal mechanisms. The review discuses the numerous approaches that have been applied to the discovery of lead small molecules that mediate biofilm development. These approaches are grouped into: (1) the identification and development of small molecules that target one of the bacterial signaling pathways involved in biofilm regulation, (2) chemical library screening for compounds with anti-biofilm activity, and (3) the identification of natural products that possess anti-biofilm activity, and the chemical manipulation of these natural products to obtain analogues with increased activity.

Synergistic Effects between Conventional Antibiotics and 2-Aminoimidazole-Derived Antibiofilm Agents

ABSTRACT 2-Aminoimidazoles are an emerging class of small molecules that possess the ability to inhibit and disperse biofilms across bacterial order, class, and phylum. Herein, we report the synergistic effect between a 2-aminoimidazole/triazole conjugate and antibiotics toward dispersing preestablished biofilms, culminating with a 3-orders-of-magnitude increase of biofilm dispersion toward Staphylococcus aureus biofilms. Furthermore, we document that the 2-aminoimidazole/triazole conjugate will also resensitize multidrug-resistant strains of bacteria to the effects of conventional antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii.

Controlling bacterial biofilms.

The ubiquitous nature of bacteria in the environment, and the role they play in infectious disease has been one of the most extensively researched areas in biomedical science. It has led to tremendous scientific breakthroughs aimed at eradicating a myriad of diseases and improving the overall quality of life. However, within the past 20–30 years, there has been an ACHTUNGTRENNUNGincreased understanding that bacterial biofilms are a major factor in the morbidity and mortality of most infectious diseases. This is significant because bacterial biofilms are resistant to common therapeutic approaches that would eliminate their free-floating (planktonic) counterparts. Biofilms are described as surface-associated communities of microorganisms encased in a protective extracellular matrix. Approximately 80 % of the world’s microbial biomass resides in the biofilm state, and the National Institutes of Health (NIH) estimates that upwards of 75 % of microbial infections that occur in the human body are underpinned by the formation and persistence of biofilms. Common diseases associated with the formation of biofilms include lung infections of individuals who suffer from cystic fibrosis (CF), burn wound infections, otitis media, bacterial endocarditis, and tooth decay (Table 1). 6] Additionally, the

Synthesis and screening of an oroidin library against Pseudomonas aeruginosa biofilms.

A 50‐compound library based on the marine natural product oroidin was synthesized and assayed for anti‐biofilm activity against PAO1 and PA14, two strains of the medically relevant γ‐proteobacterium Pseudomonas aeruginosa. Through structure–activity relationship (SAR) analysis of analogues based on the oroidin template, several conclusions can be drawn as to what structural properties of the synthetic derivatives are necessary to elicit a biological response. Notably, the most active analogues identified were those that contained a 2‐aminoimidazole (2‐AI) motif and a dibrominated pyrrolecarboxamide subunit. Here we disclose the synthesis and subsequently determined biological activity of this unique class of compounds as inhibitors of biofilm formation that have no direct antibiotic effect.

Construction and Screening of a 2‐Aminoimidazole Library Identifies a Small Molecule Capable of Inhibiting and Dispersing Bacterial Biofilms across Order, Class, and Phylum

Bacterial biofilms are defined as a surface-attached community of bacteria that are surrounded by a protective extracellular matrix. Within the biofilm state, bacteria display differential gene expression and are at least 1000-fold more resistant to antibiotic treatment. Biofilms account for more than 80% of all bacterial infections; they drive persistent infection of indwelling medical devices, and are responsible for the mortality and morbidity of almost all cystic fibrosis (CF) patients. Given the biomedical prominence of biofilms, there have been significant efforts to discover small molecules that modulate biofilm development. We have shown that simple derivatives of themarine natural product bromoageliferin will both inhibit and disperse bacterial biofilms (Scheme 1). Recently, we demonstrated that dihydrosventrin (DHS) inhibits and disperses Pseudomonas aeruginosa (multiple strains), Acinetobacter baumannii, and Bordetella bronchiseptica biofilms, making it the first small molecule reported to inhibit and disperse biofilms across bacterial order and class through a nonbactericidal mechanism. We have begun to investigate whether modifications to the core DHS structure will lead to derivatives with enhanced anti-biofilm activities. One of the first structural variations we have studied is replacement of the pyrrole subunit with a triazole subunit (Scheme 2). Herein we detail the develop-

A 2-Aminobenzimidazole That Inhibits and Disperses Gram-Positive Biofilms through a Zinc-Dependent Mechanism

A number of 2-aminobenzimidazole derivatives were synthesized and screened for their ability to inhibit and disperse bacterial biofilms. From these compounds, a lead 2-aminobenzimidazole was identified that both inhibited and dispersed MRSA, vancomycin-resistant Enterococcus faecium, and Staphylococcus epidermidis biofilms. Mechanistic studies showed that the activity is Zn(II)-dependent, potentially via a direct zinc-chelating mechanism.

Anti-Biofilm Compounds Derived from Marine Sponges

Bacterial biofilms are surface-attached communities of microorganisms that are protected by an extracellular matrix of biomolecules. In the biofilm state, bacteria are significantly more resistant to external assault, including attack by antibiotics. In their native environment, bacterial biofilms underpin costly biofouling that wreaks havoc on shipping, utilities, and offshore industry. Within a host environment, they are insensitive to antiseptics and basic host immune responses. It is estimated that up to 80% of all microbial infections are biofilm-based. Biofilm infections of indwelling medical devices are of particular concern, since once the device is colonized, infection is almost impossible to eliminate. Given the prominence of biofilms in infectious diseases, there is a notable effort towards developing small, synthetically available molecules that will modulate bacterial biofilm development and maintenance. Here, we highlight the development of small molecules that inhibit and/or disperse bacterial biofilms specifically through non-microbicidal mechanisms. Importantly, we discuss several sets of compounds derived from marine sponges that we are developing in our labs to address the persistent biofilm problem. We will discuss: discovery/synthesis of natural products and their analogues—including our marine sponge-derived compounds and initial adjuvant activity and toxicological screening of our novel anti-biofilm compounds.

Biologically inspired strategies for combating bacterial biofilms

Infections caused by bacterial biofilms are a significant global health problem, causing considerable patient morbidity and mortality and contributing to the economic burden of infectious disease. This review describes diverse strategies to combat bacterial biofilms, focusing firstly on small molecule interference with bacterial communication and signaling pathways, including quorum sensing and two-component signal transduction systems. Secondly we discuss enzymatic approaches to the degradation of extracellular matrix components to effect biofilm dispersal. Both of these approaches are based upon non-microbicidal mechanisms of action, and thereby do not place a direct evolutionary pressure on the bacteria to develop resistance. Such approaches have the potential to, in combination with conventional antibiotics, play an important role in the eradication of biofilm based bacterial infections.