Bacteria are one of the most successful colonisers of the planet. They can be found in almost all environments we know – from the deepest oceans to acid lakes, and inside and on our bodies. And the history of medicine is the struggle to defeat them.

One of the reasons for the success of bacteria is their rapid growth (some divide every 20 minutes) and ability to quickly mutate and exchange their genetic code (their DNA). These factors facilitate rapid evolution, which today has led to the emergence of drug resistance in bacteria. These bacteria eventually evolve into multi-drug resistant (MDR) bacteria, or “superbugs”, that are almost impossible to control. Some bacterial infections are so difficult to eradicate that amputation is the only option available to physicians.

But the bad news doesn’t end there.

There’s a subset of bacteria called the Gram-negative bacteria. These have an extra barrier around them (an additional membrane) that can block drug entry and that makes them ever harder to kill. Even if a drug can get in, these superbugs are often able to pump the antibiotic back out of the bacteria, or deactivate it with enzymes that render the drug useless.

Antibiotics need to be very safe to use and have minimal or no side effects. Traditionally, most antibiotics were derived from natural products isolated from different fungi and bacteria. There have been a smaller number of antibiotics that have been derived from compounds chemically synthesised in the laboratory.

But discovering non-toxic, novel antibiotics from bacteria and fungi has become increasingly difficult as exhaustive searches for new sources of natural products have been going on for more than 70 years. The alternative – chemically synthesised molecules – have their own problems, as many cannot reach their biological target inside the bacteria due to the barriers mentioned above.

One way to control superbugs is to develop new antibiotics that kill through a different mechanism to existing drugs. But there have been only five new chemical classes of antibiotics launched since 1970 – linezolid (2000) and daptomycin (2003) for systemic infections, mupirocin (1985) and retapamulin (2007) for topical infections, and the recent approval of fidaxomicin (2012) for the treatment of gut infections caused by Clostridium difficile.

Before a new drug is approved, it needs to go through laboratory (pre-clinical) testing and clinical development (testing in humans). Drugs still in testing at these stages, which are not yet approved for sale, form the “antibiotic pipeline”.

Two major organisations, the Infectious Diseases Society of America (IDSA) and European Centre for Disease Prevention and Control have analysed the antibiotic pipeline and concluded there are only a few potential drugs offering significant benefits over existing drugs. More alarmingly, there are very few antibiotics that are able to treat Gram-negative infections, such as NDM-1 bacteria.

This prompted us to analyse antibiotics in clinical development and those launched into the market since 2000. We found that there were an equal number of natural product-derived and chemically synthesised compounds in early clinical development. But, with the exception of just one class of antibiotic called the fluoroquinolones, natural product-derived compounds predominate in late stage clinical development.

There are still only a few compounds in the pipeline able to treat fluoroquinolone-resistant Gram-negative superbugs – Tetraphase’s tetracyclines TP-434 and TP-2758, Basilea’s monobactam-siderophore hybrid BAL30072 and the Achaogen’s aminoglycoside ACHN-490.

The antibiotic pipeline for the treatment of Gram-positive infections is a little brighter, and many of these compounds look likely to be able to help treat today’s Gram-positive superbugs. But it should be noted that many patients infected with these superbugs, such as MRSA, still die in hospital, especially if the bacteria is circulating the blood (septicaemia).

So where does this leave us?

The introduction of antibiotics more than 70 years ago escalated the conflict between humans and pathogens to code red. Although we seemed to be winning the war for the first 40 years, the rear guard action of superbugs in the last 20 years has left us reeling and, in some cases, defenceless.

It’s hard to fathom why we have accelerated the rise of the superbugs through the indiscriminate use of antibiotics in medicine and agriculture. Unfortunately, this is not a normal war with an armistice or surrender, as these pathogens will be fighting us for eternity.

There are no magic bullets in the antibiotic pipeline that will eradicate all superbugs. Although the discovery of new antibiotics is not a trivial task, as a society we must rise to the challenge and take action to find new and improved antibiotics, in addition to innovative ways to control these bacteria today or risk a future returned to the pre-antibiotic age.

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This is the final article in Superbugs vs Antibiotics, a series examining the rise of antibiotic-resistant superbugs. Click on the links below to read the other instalments.

Part one: Washing our hands of responsibility for hospital infections

Part two: Superbugs, human ecology and the threat from within

Part three: We can beat superbugs with better stewardship of antibiotics

Part four: The hunt is on for superbugs in Australian animals

Part five: The last stand: the strongest of the superbugs and their antibiotic nemesis

Part six: Unblocking the pipeline for new antibiotics against superbugs

Part seven: A peek at a world with useless antibiotics and superbugs

Part eight: Trading chemistry for ecology with poo transplants