Double strike against bacteria and viruses

Agent inhibits the AIDS pathogen and resistant MRSA bacteria

11.07.2016

Staphylococcus aureus bacteria (red) often develop resistance to antibiotics. Methicillin-resistant Staphylococcus aureus strains (MRSA) especially threaten patients that are already infected with…

© HZI/M. RohdeStaphylococcus aureus bacteria (red) often develop resistance to antibiotics. Methicillin-resistant Staphylococcus aureus strains (MRSA) especially threaten patients that are already infected with HIV.

A new class of substances is effective against both the AIDS pathogen, HIV, and antibiotics-resistant MRSA bacteria. These two pathogens often occur together. Scientists hope that it may be possible to control them with a single drug in the future. Scientists of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) developed so-called dual agents that inhibit the growth of both types of pathogens. They describe their findings in the renowned Journal of Medicinal Chemistry. The HIPS is the Saarbrücken branch of the Helmholtz Centre for Infection Research (HZI), which has its headquarters in Braunschweig. It was founded jointly by the HZI and Saarland University in 2009.

The human immunodeficiency virus HIV is one of the most dangerous and widespread pathogens throughout the world. Some 37 million people are host to the virus and 1.2 million were killed by this disease in 2014 alone. Meanwhile, both the proliferation of the pathogen and the progression of the disease can be halted through a combination therapy, but the viruses show an increasing trend to develop resistance and no longer respond to the medications used against them.

The notorious MRSA bacteria, i.e. methicillin-resistant Staphylococcus aureus strains, show similar persistence as many common antibiotics have become ineffective. HIV patients, whose immune system has already been weakened by the disease, are often additionally afflicted by MRSA pathogens. These co-infections are very problematic and difficult to treat. "Resistance to the common therapies is quite widespread amongst both the viruses and the MRSA bacteria, which means that the co-infection is very difficult to control," explains HZI scientist Prof Rolf Hartmann, who is the head of the "Drug Design and Optimization" department at the HIPS. "In addition, it is necessary to carefully consider the interactions between the medications given to the patients."

Schnitt durch die Schichten des HI-Virus mit Blick auf das Erbmaterial im Inneren des Virus.

Helmholtz-HZI/Britta MeyerAIDS, Erreger, Grafik, HIV, Impfstoffforschung, Schmuckbild, WissFoto

Ureidothiophene carboxylic acids may be a remedy for this issue. The complicated name stands for a class of molecules that has been expanded by the medicinal chemists and bioscientists at the HIPS to include several new members. These new members include some novel agents that block the proliferation of both HIV and MRSA. Interestingly: "Strains known to be resistant are sensitive to our dual agents - both viral and bacterial strains," explains Walid Elgaher, who works at the HIPS. "We have not detected any harmful effect on human cells as of yet."

Although viruses and bacteria are very different in terms of their biochemistry, the observed effect, i.e. the inhibition of the growth of both types of pathogen by a single agent, can be explained rationally. HI viruses and the bacteria use certain specialised enzymes for their growth and proliferation in order to "re-code" their genetic information basically translating it from one language to another. These enzymes are protein molecules with a catalytic effect and resemble each other in terms of their function and structure.

In the bacteria, the RNA polymerase enzyme translates the genetic information from the deoxyribonucleic acid (DNA) form to the ribonucleic acid (RNA) form, which then contains the blueprint for the major components of the bacterial cell. HIV, the AIDS pathogen, needs the reverse transcriptase enzyme for its lifecycle as this enzyme triggers the reverse process and converts RNA to DNA.

A dual agent (top) inhibits both a viral enzyme – the HIV reverse transcriptase (left) – and a bacterial enzyme – the Staphylococcus aureaus RNA polymerase (right).

© HZI / W. A. M. ElgaherA dual agent (top) inhibits both a viral enzyme – the HIV reverse transcriptase (left) – and a bacterial enzyme – the Staphylococcus aureaus RNA polymerase (right).

Scientists noted years ago that the RNA polymerase of certain bacteria and the reverse transcriptase of the AIDS pathogen comprise similar chemical binding sites - and therefore might be blocked and inhibited jointly. The HIPS scientists made use of this information: "We developed several substances that can inhibit the RNA polymerase of bacteria such as MRSA," HZI researcher Dr Jörg Haupenthal explains. "We optimised these substances so that they dock to very similar binding sites of the HI viruses and block them."

The scientists hope that their discovery can be utilised for clinical applications in the future. "For this purpose, we have to carefully check, if the substances are also effective in the cell and ultimately in human patients and if there are adverse effects after all," explains Rolf Hartmann. "This will require comprehensive studies and development."

 

Original publication:

Walid A. M. Elgaher, Kamal Kant Sharma, Jörg Haupenthal, Francesco Saladini, Manuel Pires, Eleonore Real, Yves Mély, and Rolf W. Hartmann: Discovery and Structure-Based Optimization of 2 Ureidothiophene-3-Carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors. J. Med. Chem. DOI: 10.1021/acs.jmedchem.6b00730

dx.doi.org/10.1021/acs.jmedchem.6b00730

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